JP2021509398A - Dual-acting FKBP12 and FKBP52 inhibitors - Google Patents

Abstract

Provided are novel compounds of formulas (I) and (II) useful as dual FKBP12 / FKABP inhibitors, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Pharmaceutical compositions comprising novel compounds of formulas (I) and (II), and their use in the treatment of Parkinson's disease are also provided. [Selection diagram] FIG. 6C-D

Description

With respect to novel compounds useful as dual-acting FKBP12 / FKABP inhibitors, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. It also relates to pharmaceutical compositions containing the novel compounds and their use in the treatment of Parkinson's disease.

Cross-reference to related applications This application is a US patent application number entitled "Benzimidazole Derivatives as Dual Action FKBP12 and FKBP52 Inhibitors" filed on August 21, 2017, both of which are: Claims benefits under Article 35 USC §119 of US Provisional Patent Application No. 62 / 547,977, entitled 62 / 547,976, and "Double Action FKBP12 and FKBP52 Inhibitors". The disclosures of these applications are incorporated herein by reference in their entirety.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. In the United States alone, 50,000 to 60,000 new cases of PD are diagnosed each year, in addition to the approximately 1 million patients currently living with PD. Importantly, no treatment is currently available to stop or restore neurodegeneration of PD.

Parkinson's disease (PD) is characterized by degeneration of substantia nigra dopaminergic neurons. A characteristic of PD neurodegeneration is the abnormal aggregation of α-synuclein (a-SYNC). In PD, proteins are present in fibrous aggregates inside intracellular inclusion bodies called Lewy bodies. Enzymes of the FK506 binding protein (FKBP) family promote the aggregation of recombinant a-SYNC in vitro, and the specific FKBP inhibitor FK506 negates this effect (Gerard et al. 2006, 2008).

FKBP is a member of the immunophyllin family of proteins. These proteins are enzymes with peptidyl-prolyl cis-transisomerase (PPlas) activity that bind to immunosuppressive agents such as FK506 (Gothel and Marahiel, 1999). The Pplace enzyme catalyzes the cis-trans isomerization of X-Pro peptide bonds, which is an essential and rate-determining step in the process of protein folding. The human FKBP family includes 15 key members with different functions (Galat, 2003; Rulten et al, 2006). Of these, four members, FKBP12, FKBP38, FKBP52, and FKBP65, are enriched in the human brain (Steiner et al., 1992; Charters et al., 1994 a, b). Importantly, numerous clinical and preclinical studies have demonstrated that two FKPBs, FKBP12 and FKPB52, are involved in PD pathology. Recent experimental studies have shown that FKBP 12 and FKBP 52 strongly promote the formation of a-SYNC aggregates present in Lewy bodies (LB), which is characteristic of PD pathology (Deleersnijder, A. et al. et al., 2011; and Gerard, M. et al., 2011). Immunophyllins other than FKBP 12/52, including FKBP 38, FKBP 51, and FKBP 65, are also enriched in the brain, accelerating a-SYNC aggregation, but to a lesser extent (Chattopadhaya, S. et al., 2012). In a neural model of synucleopathies, inhibition by FKBP 12/52 knockdown or FK506 (a potent immunosuppressant of FKBP) can counteract the effects of oxidative stress, but its overexpression promotes a-SYN aggregation. (Deleersnijder, A. et al., 2011; Gerard, M. 2010).

Their regulation not only promotes the regeneration of spare dopaminergic (DA) neurons, but also protects existing neurons from further neurodegeneration. Sequence alignment based on the homology of the FK506 binding domains of FKBP12 and FKBP52 shows 53% overall identity. Interestingly, detailed analysis based on structural superposition reveals that there is 82% identity within the 8A radius of the ligand binding site.
Currently, there is no cure for stopping or ameliorating the neurodegeneration of PD, so it is necessary to develop new therapeutic agents that can prevent such degeneration.

または、その薬学的に活性な塩が含まれ、式中、式（Ｉ）のＲ^１、Ｒ^２、Ｒ^３、Ｒ^６、および式（ＩＩ）のＲ^１、Ｒ^２およびＲ^３は、本明細書で定義されるとおりである。 The compounds described herein and their pharmaceutically acceptable compositions have now been found to be effective dual action inhibitors of FKBP12 and FKBP52. Such compounds include those of the following formulas (I) and (II):

Or its being pharmaceutically includes active salts, ^{R 1,} R ^2, R 3, ^{R 6,} and ^R 1, ^{R 2} and ^{R 3} of formula (II) in the formula, the formula (I), the present As defined in the specification.

The compounds provided and pharmaceutically acceptable compositions thereof are inhibitors of the dual action of FKBP12 and FKBP52 and are useful in the treatment of Parkinson's disease.
The compounds provided can be used alone (ie, as a monotherapy) or in combination with one or more other therapeutic agents effective in treating Parkinson's disease.
Details of the present invention are described in the following description. Other features, objectives, and advantages of the present invention will become apparent from the detailed description of some embodiments below and the appended claims.

FIG. 1A shows the administration of the double-acting FKBP12 and FKBP52 inhibitory compound CAP01687 to PC12 rat chromaffin cell tumor cells PC12 in a model of 6-hydroxydopamine (6-OHDA) that induces Parkinson's disease. It is one bar graph which shows the nerve protection which occurs. FIG. 1B results from administration of the dual-acting FKBP12 and FKBP52 inhibitory compound CAP01693 to PC12 rat chromaffin cell tumor cells PC12 in a model of 6-hydroxydopamine (6-OHDA) that induces Parkinson's disease. Another bar graph showing neuroprotection is a set with that of FIG. 1A. FIG. 2 is a bar graph showing the promotion of neurite outgrowth by the exemplary compound CAP01687, which inhibits dual-acting FKBP12 and FKBP52. FIG. 3A shows the neuroprotection resulting from administration of the dual action FKBP12 and FKBP52 inhibitory compound CAP01687 to wild-type α-synuclein overexpressing BE (2) -M17 cells, as measured by the Aramar Blue assay. It is a bar graph. FIG. 3B shows the dual effect FKBP12 and FKBP52 inhibitory exemplary compound CAP01687 on the A53T mutant α-synuclein overexpressing BE (2) -M17 cells (M3.2), also measured in the Aramar Blue assay. It is a bar graph which shows the neuroprotection resulting from administration. FIG. 4A shows neuroprotection in wild-type α-synuclein overexpressing cells (WT21) resulting from treatment of cells with the exemplary compound CAP01551, which inhibits dual-acting FKBP12 and FKBP52, as measured by the Aramar Blue assay. It is a bar graph. FIG. 4B is a bar graph showing neuroprotection in WT21 cells resulting from treating cells with the double-acting FKBP12 and FKBP52 inhibitory exemplary compound CAP01559, as measured by the Aramar Blue assay. FIG. 5 overexpresses BE (2) -M17 cells (M3.2) resulting from treatment of cells with the exemplary compound CAP01559, which inhibits dual-acting FKBP12 and FKBP52, as measured by the Aramar Blue assay. It is a bar graph which shows the neuroprotection in A53T mutation α-synuclein. FIG. 6A is a bar graph showing that the exemplary compound CAP01324 is not cytotoxic to WT21 cells at concentrations below 50 μM as determined by the observed relative changes in absorbance during reduction of the MTS tetrazolium dye. FIG. 6B is a bar graph showing neuroprotection in A53T mutant cells conferred by CAP01324 (100 nM), as determined by the observed relative changes in absorbance during reduction of the MTS tetrazolium dye. FIG. 6C shows light microscope images of neurite outgrowth of PC12 cells treated with control (DMSO) and the exemplary compound CAP01510 that inhibits FKBP12 and FKBP52. FIG. 6D is a bar graph showing the dose-dependent promotion of neurite outgrowth by exemplary CAP01510 with dual-acting FKBP12 and FKBP52 inhibitors.

またはその薬学的に許容し得る塩を提供し、式中、Ｒ^１は、Ｒ^４から独立して選択される１つ以上の基で任意に置換されたシクロアルキル、アリール、またはヘテロアリール基であり、Ｒ^４は、（Ｃ_１−Ｃ_６）アルキル；ハロ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_２−Ｃ_６）アルケニル；ハロ（Ｃ_２−Ｃ_６）アルケニル；（Ｃ_２−Ｃ_６）アルキニル；ハロ（Ｃ_２−Ｃ_６）アルキニル；（Ｃ_１−Ｃ_６）アルコキシ；ハロ（Ｃ_１−Ｃ_６）アルコキシ；（Ｃ_１−Ｃ_６）アルキルチオ；ハロ（Ｃ_１−Ｃ_６）アルキルチオ；（Ｃ_１−Ｃ_６）アルキルスルフィニル；ハロ（Ｃ_１−Ｃ_６）アルキルスルフィニル; （Ｃ_３−Ｃ_６）シクロアルキルスルフィニル；ハロ（Ｃ_３−Ｃ_６）シクロアルキルスルフィニル；（Ｃ_１ −Ｃ_６）アルキルスルホニル；ハロ（Ｃ_１−Ｃ_６）アルキルスルホニル；（Ｃ_３−Ｃ_６）シクロアルキルスルホニル；ハロ（Ｃ_３−Ｃ_６）シクロアルキルスルホニル；（Ｃ_１−Ｃ_６）アルキルアミノ；ジ（Ｃ_１−Ｃ_６）アルキルアミノ; （Ｃ_１−Ｃ_６）アルコキシ（Ｃ_１−Ｃ_６）アルコキシ；ハロ（Ｃ_１−Ｃ_６）アルコキシ（Ｃ_１−Ｃ_６）アルコキシ；（Ｃ_１ −Ｃ_６）アルコキシカルボニル;アミノカルボニル；Ｈ２ＮＳＯ２；（Ｃ_１−Ｃ_６）アルキルアミノカルボニル；ジ（Ｃ_１−Ｃ_６）アルキルアミノカルボニル；（Ｃ_１−Ｃ_３）アルコキシ（Ｃ_１ −Ｃ_３）アルキルアミノカルボニル；ヘテロシクリルカルボニル；（Ｃ_１−Ｃ_６）アルキルアミノスルホニル、ジ（Ｃ_１−Ｃ_６）アルキルアミノスルホニル;ヘテロシクリルスルホニル；（Ｃ_１ −Ｃ_６）アルキルカルボニルアミノ；（Ｃ_１−Ｃ_６）アルキルカルボニルアミノ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_１ −Ｃ_６）アルキルスルホニルアミノ；（Ｃ_１−Ｃ_６）アルキルスルホニルアミノ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_１−Ｃ_６）アルコキシカルボニル（Ｃ_１−Ｃ_６）アルコキシ；（Ｃ_１−Ｃ_６）アルコキシ（Ｃ_１−Ｃ_６）アルキル、ハロ（Ｃ_１−Ｃ_６）アルコキシ（Ｃ_１−Ｃ_６）アルキル；ヒドロキシ（Ｃ_１ −Ｃ_６）アルコキシ；アミノ（Ｃ_１ −Ｃ_６）アルキル；（Ｃ_１−Ｃ_６）アルキルアミノ（Ｃ_１ −Ｃ_６）アルキル；ジ（Ｃ_１−Ｃ_６）アルキルアミノ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_１−Ｃ_６）アルキルアミノ（Ｃ_２−Ｃ_６）アルコキシ；ジ（Ｃ_１−Ｃ_６）アルキルアミノ（Ｃ_２−Ｃ_６）アルコキシ；（Ｃ_１−Ｃ_６）アルキルカルボニル；ヒドロキシ（Ｃ_１ −Ｃ_６）アルキルカルボニル；（Ｃ_１ −Ｃ_６）アルキルヒドロキシカルボニル；（Ｃ_１ −Ｃ_６）アルキルヒドロキシ（Ｃ_１ −Ｃ_６）アルキル；（Ｃ_３−Ｃ_６）シクロアルキルカルボニル；（Ｃ_３−Ｃ_６）シクロアルキルアミノカルボニル；｛（Ｃ_３−Ｃ_６）シクロアルキル｝｛（Ｃ_１−Ｃ_６）アルキル｝アミノカルボニル；ジ（Ｃ_３−Ｃ_６）シクロアルキルアミノカルボニル；（Ｃ_３−Ｃ_６）シクロアルキルアミノスルホニル；｛（Ｃ_３−Ｃ_６）シクロアルキル｝｛（Ｃ_１−Ｃ_６）アルキル｝アミノスルホニル；ジ（Ｃ_３−Ｃ_６）シクロアルキルアミノスルホニル；シアノ（Ｃ_１ −Ｃ_６）アルキル；アミノカルボニル（Ｃ_１ −Ｃ_６）アルキル；（Ｃ_１ −Ｃ_６）アルキルアミノカルボニル（Ｃ_１−Ｃ_６）アルキル；ジ（Ｃ_１ −Ｃ_６）アルキルアミノカルボニル（Ｃ_１−Ｃ_６）アルキル；（Ｃ_３−Ｃ_６）シクロアルキルアミノカルボニル（Ｃ_１−Ｃ_６）アルキル；｛（Ｃ_３−Ｃ_６）シクロアルキル｝｛（Ｃ_１−Ｃ_６）アルキル｝アミノカルボニル（Ｃ_１−Ｃ_６）アルキル；［Ｃ_１−Ｃ_６）アルキル（Ｃ_４−Ｃ_６）ヘテロシクリル］（Ｃ_１−Ｃ_６）アルキル；およびジ（Ｃ_３−Ｃ_６）シクロアルキルアミノカルボニル（Ｃ_１−Ｃ_６）アルキルから選択され；
Ｒ^２は、Ｒ^５から独立して選択される１つ以上の基で任意に置換されたシクロアルキルまたは芳香環であり；
Ｒ^３、Ｒ^４、およびＲ^５はハロ；シアノ；ニトロ；アミノ；ヒドロキシ；カルボキシ； （Ｃ_１ −Ｃ_６）アルキル；ハロ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_１−Ｃ_６）ヒドロキシアルキル；（ＣＨ_２）_１−３ＣＯＯＨ；（Ｃ_１−Ｃ_６）アルコキシ；ハロ（Ｃ_１−Ｃ_６）アルコキシ；（Ｃ_１−Ｃ_６）アルキルチオ；ハロ（Ｃ_１−Ｃ_６）アルキルチオ；（Ｃ_１−Ｃ_６）アルキルスルフィニル；ハロ（Ｃ_１ −Ｃ_６）アルキルスルフィニル；（Ｃ_１ −Ｃ_６）アルキルスルホニル；ハロ（Ｃ_１−Ｃ_６）アルキルスルホニル；（Ｃ_１−Ｃ_６）アルキルアミノ；ジ（Ｃ_１−Ｃ_６）アルキルアミノ；（Ｃ_２−Ｃ_４）アルコキシカルボニル；（Ｃ_２−Ｃ_４）アルキルアミノカルボニル；ジ（Ｃ_２−Ｃ_４）アルキルアミノカルボニル；（Ｃ_３−Ｃ_６）シクロアルキル；ハロ（Ｃ_３−Ｃ_６）シクロアルキル；（Ｃ_３−Ｃ_６）シクロアルコキシ；ハロ（Ｃ_３−Ｃ_６）シクロアルコキシ；ハロゲン、ＯＨ、またはＮＨ_２で置換されていてもよいアリール；アリールオキシ；（Ｃ_１−Ｃ_６）アルキルチオ；ハロ（Ｃ_１−Ｃ_６）アルキルチオ；（Ｃ_３−Ｃ_６）シクロアルキルチオ；ハロ（Ｃ_３−Ｃ_６）シクロアルキルチオ；（Ｃ_１−Ｃ_６）アルキルアミノ；およびジ（Ｃ_１−Ｃ_６）アルキルアミノ基から独立して選択され、
Ｒ^６は水素、（Ｃ_１−Ｃ_６）アルキル、またはハロ（Ｃ_１−Ｃ_６）アルキルであり、ＸはＯまたはＮＨであり、
ＺはＣＨ_２またはＣ＝０であり、
ｎは０〜４の数値であり、
ｐは１〜５の数値であり、
ＢおよびＹは、独立してＣＨまたはＮである。 Detailed explanation 1. General Description of Compounds In certain embodiments, the present disclosure describes compounds of formula (I):

Alternatively, providing a pharmaceutically acceptable salt thereof, in the formula, R ¹ is a cycloalkyl, aryl, or heteroaryl group optionally substituted with one or more groups independently selected from ^{R 4.} Yes, R ⁴ is (C _1- C ₆ ) alkyl; halo (C _1- C ₆ ) alkyl; (C _2- C ₆ ) alkenyl; halo (C _2- C ₆ ) alkenyl; (C _2- C ₆₎ ) Alkinyl; halo (C _2- C ₆ ) alkynyl; (C _1- C ₆ ) alkoxy; halo (C _1- C ₆ ) alkoxy; (C _1- C ₆ ) alkyl thio; halo (C _1- C ₆ ) alkyl thio (C _1- C ₆ ) Alkyl Sulfinyl; Halo (C _1- C ₆ ) Alkyl Sulfinyl; (C _3- C ₆ ) Cycloalkyl Sulfinyl; Halo (C _3- C ₆ ) Cycloalkyl Sulfinyl; (C _1- C 6) ₆ ) Alkylsulfonyl; halo (C _1- C ₆ ) alkyl sulfonyl; (C _3- C ₆ ) cycloalkyl sulfonyl; halo (C _3- C ₆ ) cycloalkyl sulfonyl; (C _1- C ₆ ) alkyl amino; di (C _1- C ₆ ) Alkylamino; (C _1- C ₆ ) Ekoxy (C _1- C ₆ ) Ekoxy; Halo (C _1- C ₆ ) Ekoxy (C _1- C ₆ ) Ekoxy; (C _{1-C 6) Ekoxy; 6} ) alkoxycarbonyl; aminocarbonyl; H2NSO2; (C _1- C ₆ ) alkylaminocarbonyl; di (C _1- C ₆ ) alkyl aminocarbonyl; (C _1- C ₃ ) alkoxy (C _1- C ₃ ) alkyl amino carbonyl; _{heterocyclylcarbonyl; (C} 1 -C ₆₎ alkylaminosulfonyl, di _(C 1 -C ₆₎ alkyl aminosulfonyl; _{heterocyclylsulfonyl; (C} 1 -C _{6) alkylcarbonylamino; (C} 1 -C ₆₎ alkyl Carbonylamino (C _1- C ₆ ) Alkyl; (C _1- C ₆ ) Alkylsulfonylamino; (C _1- C ₆ ) Alkylsulfonylamino (C _1- C ₆ ) Alkyl; (C _1- C ₆ ) Alkoxycarbonyl (C _1- C ₆ ) alkoxy; (C _1- C ₆ ) alkoxy (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkoxy (C _1- C ₆ ) al. Kill; hydroxy (C _1- C ₆ ) alkoxy; amino (C _1- C ₆ ) alkyl; (C _1- C ₆ ) alkyl amino (C _1- C ₆ ) alkyl; di (C _1- C ₆ ) alkyl amino (C _1- C ₆ ) alkyl; (C _1- C ₆ ) alkyl amino (C _2- C ₆ ) alkoxy; di (C _1- C ₆ ) alkyl amino (C _2- C ₆ ) alkoxy; (C _{1-C 6)} C ₆ ) Alkyl carbonyl; Hydroxy (C _1- C ₆ ) Alkyl carbonyl; (C _1- C ₆ ) Alkyl hydroxy carbonyl; (C _1- C ₆ ) Alkyl hydroxy (C _1- C ₆ ) Alkyl; (C _{3-C 6) Alkyl;} C ₆ ) Cycloalkylcarbonyl; (C _3- C ₆ ) Cycloalkylaminocarbonyl; {(C _3- C ₆ ) Cycloalkyl} {(C _1- C ₆ ) Alk} Aminocarbonyl; Di (C _3- C ₆₎ ) Cycloalkylaminocarbonyl; (C _3- C ₆ ) cycloalkyl aminosulfonyl; {(C _3- C ₆ ) cycloalkyl} {(C _1- C ₆ ) alkyl} aminosulfonyl; di (C _3- C ₆ ) Cycloalkylaminosulfonyl; cyano (C _1- C ₆ ) alkyl; aminocarbonyl (C _1- C ₆ ) alkyl; (C _1- C ₆ ) alkyl aminocarbonyl (C _1- C ₆ ) alkyl; di (C _{1-C 6) alkyl} C ₆ ) Alkylaminocarbonyl (C _1- C ₆ ) Alkyl; (C _3- C ₆ ) Cycloalkyl Aminocarbonyl (C _1- C ₆ ) Alkyl; {(C _3- C ₆ ) Cycloalkyl} {(C ₁₎ -C ₆ ) Alkyl} Aminocarbonyl (C _1- C ₆ ) Alkyl; [C _1- C ₆ ) Alkyl (C _4- C ₆ ) Heterocyclyl] (C _1- C ₆ ) Alkyl; and Di (C _3- C 6) Alkyl; ₆ ) Cycloalkyl Aminocarbonyl (C _1- C ₆ ) Selected from alkyl;
R ² is a cycloalkyl or aromatic ring optionally substituted with one or more groups independently selected from ^{R 5;}
R ³ , R ⁴ , and R ⁵ are halo; cyano; nitro; amino; hydroxy; carboxy; (C _1- C ₆ ) alkyl; halo (C _1- C ₆ ) alkyl; (C _1- C ₆ ) hydroxyalkyl _{; (CH 2) 1-3 COOH;} (C 1 -C 6) alkoxy; halo _(C 1 -C _{6) alkoxy; (C} 1 -C ₆₎ alkylthio; halo _(C 1 -C ₆₎ alkylthio; (C _1- C ₆ ) Alkoxy sulfinyl; Halo (C _1- C ₆ ) Alkoxy sulfinyl; (C _1- C ₆ ) Alkoxy sulfonyl; Halo (C _1- C ₆ ) Alkoxy sulfonyl; (C _1- C ₆ ) Alkoxy amino; Di (C _1- C ₆ ) alkylamino; (C _2- C ₄ ) alkoxycarbonyl; (C _2- C ₄ ) alkyl aminocarbonyl; di (C _2- C ₄ ) alkyl aminocarbonyl; (C _3- C ₆₎ ) Cycloalkyl; halo (C _3- C ₆ ) cycloalkyl; (C _3- C ₆ ) cycloalkoxy; halo (C _3- C ₆ ) cycloalkoxy; may be substituted with halogen, OH, or NH _2. Aryl; aryloxy; (C _1- C ₆ ) alkylthio; halo (C _1- C ₆ ) alkyl thio; (C _3- C ₆ ) cycloalkyl thio; halo (C _3- C ₆ ) cycloalkyl thio; (C _{1-C 6) 6)} alkylamino; and di _(C 1 -C ₆₎ independently of the alkylamino group is selected,
R ⁶ is hydrogen, (C _1- C ₆ ) alkyl, or halo (C _1- C ₆ ) alkyl, X is O or NH,
Z is CH ₂ or C = 0,
n is a numerical value from 0 to 4,
p is a numerical value of 1 to 5,
B and Y are independently CH or N.

の化合物またはその薬学的に許容し得る塩を提供し、
式中、Ｒ^１およびＲ^３のそれぞれは、水素；ハロゲン；ニトロ；シアノ；アミノ；ヒドロキシ；カルボキシ；（Ｃ_１−Ｃ_６）アルキル；ハロ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_１−Ｃ_６）アルコキシ；ハロ（Ｃ_１−Ｃ_６）アルコキシ；（Ｃ_３−Ｃ_１０）シクロアルキル；ハロ（Ｃ_３−Ｃ_１０）シクロアルキル；（Ｃ_３−Ｃ_１０）シクロアルキルチオ；ハロ（Ｃ_３−Ｃ_１０）シクロアルキルチオ；（Ｃ_３−Ｃ_１０）ヘテロシクロアルキル；ハロ（Ｃ_３−Ｃ_１０）ヘテロシクロアルキル；（Ｃ_１−Ｃ_６）アルキルアミノ；ジ（Ｃ_１−Ｃ_６）アルキルアミノ；（Ｃ１−Ｃ_６）アルキルチオ；ハロ（Ｃ_１−Ｃ_６）アルキルチオ；（Ｃ_１−Ｃ_６）アルキルスルフィニル；ハロ（Ｃ_１−Ｃ_６）アルキルスルフィニル；（Ｃ_１−Ｃ_６）アルキルスルホニル；ハロ（Ｃ_１−Ｃ_６）アルキルスルホニル；（Ｃ_３−Ｃ_１０）シクロアルキルスルフィニル；ハロ（Ｃ_３−Ｃ_１０）シクロアルキルスルフィニル；（Ｃ_３−Ｃ_１０）シクロアルキルスルホニル；ハロ（Ｃ_３−Ｃ_１０）シクロアルキルスルホニル；ハロゲン、ニトロ、シアノ、アミノ、ヒドロキシ、カルボキシ、（Ｃ_１−Ｃ_６）アルキル、ハロ（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルコキシ、またはハロ（Ｃ_１−Ｃ_６）アルコキシ；関連するフェニル環、いずれか１つの環はハロゲン、ニトロ、シアノ、アミノ、ヒドロキシ、カルボキシ、（Ｃ_１−Ｃ_６）アルキル、ハロ（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルコキシ、ハロ（Ｃ_１−Ｃ_６）アルコキシまたはアリールアミンで任意に置換されている、に融合したアリール環からなる群より独立して選択され、
Ｘ−ＹはＣ＝Ｃ、Ｃ≡Ｃ、またはＮ＝Ｎであり、
Ｒ^２は、（Ｃ_１−Ｃ_６）アルキル；ハロ（Ｃ_１−Ｃ_６）アルキル；（Ｃ_２−Ｃ_６）アルケニル；ハロ（Ｃ_２−Ｃ_６）アルケニル；（Ｃ_２−Ｃ_６）アルキニル；ハロ（Ｃ_２−Ｃ_６）アルキニル；（Ｃ_３−Ｃ_１０）シクロアルキル；ハロ（Ｃ_３−Ｃ_１０）シクロアルキル；ヘテロシクリル、アリール、またはヘテロアリールからなる群から選択され、それぞれハロゲン、ニトロ、シアノ、アミノ、ヒドロキシ、カルボキシ、（Ｃ_１−Ｃ_６）アルキル、ハロ（Ｃ_１−Ｃ_６）アルキル、（Ｃ_１−Ｃ_６）アルコキシ、およびハロ（Ｃ_１−Ｃ_６）アルコキシから独立して選択される１つ以上の基で任意に置換され;そしてｍは０〜４である。 In certain other embodiments, the present disclosure is a formula.

To provide a compound of or a pharmaceutically acceptable salt thereof,
In the formula, ^{each of R 1} and R ³ is hydrogen; halogen; nitro; cyano; amino; hydroxy; carboxy; (C _1- C ₆ ) alkyl; halo (C _1- C ₆ ) alkyl; (C _1- C) ₆ ) Alkoxy; Halo (C _1- C ₆ ) Alkoxy; (C _3- C ₁₀ ) Cycloalkyl; Halo (C _3- C ₁₀ ) Cycloalkyl; (C _3- C ₁₀ ) Cycloalkyl thio; Halo (C _{3-C 10)} C ₁₀ ) Cycloalkylthio; (C _3- C ₁₀ ) Heterocycloalkyl; Halo (C _3- C ₁₀ ) Heterocycloalkyl; (C _1- C ₆ ) Alkoxy Amino; Di (C _1- C ₆ ) Alkoxy Amino; _{(C1-C 6)} alkylthio; halo _(C 1 -C _{6) alkylthio; (C} 1 -C ₆₎ alkylsulfinyl; halo _(C 1 -C _{6) alkylsulfinyl; (C} 1 -C ₆₎ alkylsulfonyl; halo (C _1- C ₆ ) Alkoxysulfonyl; (C _3- C ₁₀ ) Cycloalkyl Sulfinyl; Halo (C _3- C ₁₀ ) Cycloalkyl Sulfinyl; (C _3- C ₁₀ ) Cycloalkyl sulfonyl; Halo (C _3- C 10) ₁₀ ) Cycloalkylsulfonyl; halogen, nitro, cyano, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, or halo (C 1-C 6) alkoxy. _1- C ₆ ) Alkoxy; related phenyl rings, any one of which is halogen, nitro, cyano, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkyl, ( Selected independently from the group consisting of aryl rings fused to C _1- C ₆ ) alkoxy, halo (C _1- C _{6) alkoxy or arylamine optionally substituted,}
XY is C = C, C≡C, or N = N,
R ² _{is, (C} 1 -C ₆₎ alkyl; halo _(C 1 -C _{6) alkyl; (C} 2 -C ₆₎ alkenyl; halo _(C 2 -C _{6) alkenyl; (C} 2 -C ₆₎ alkynyl Halo (C _2- C ₆ ) alkynyl; (C _3- C ₁₀ ) cycloalkyl; halo (C _3- C ₁₀ ) cycloalkyl; selected from the group consisting of heterocyclyl, aryl, or heteroaryl, halogen, nitro, respectively. , Cyan, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, and halo (C _1- C ₆ ) alkoxy independent. Arbitrarily substituted with one or more groups selected; and m is 0-4.

2. Compounds and Definitions The terms "halo" and "halogen" as used herein refer to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodine, -I) means an atom selected from.
The term "alkyl", used alone or as part of a larger portion such as "haloalkyl", is a saturated monovalent linear or branched hydrocarbon radical with 1-10 carbon atoms unless otherwise specified. Means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, Includes n-decyl and the like. "Monovalent" means that at one point it is bound to the rest of the molecule.

The term "cycloalkyl", used alone or as part of a larger portion, is described herein as a saturated cyclic aliphatic monocyclic, having 3 to 10 carbocyclic atoms, unless otherwise stated. , Bicyclic or tricyclic ring system. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bicyclic cycloalkyl groups include aryl groups such as decalin or tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroisoquinolin (eg, phenyl). Alternatively, it includes a cycloalkyl group fused with another cycloalkyl group, such as a cycloalkyl group fused with a heteroaryl group. An example of a tricyclic is adamantane. It will be appreciated that the attachment point of a bicyclic cycloalkyl group can be either a cycloalkyl moiety, or an aryl group (eg, phenyl) or a heteroaryl group that provides a stable structure. Further, if specified, it will be appreciated that any substituent on the cycloalkyl may be present at any substitutable position, including, for example, the position to which the cycloalkyl binds.

The term "heterocyclyl" means a 4, 5, 6 and 7-membered saturated or partially unsaturated heterocycle containing 1 to 4 heteroatoms independently selected from N, O, and S. The "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" can be used interchangeably. The heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that provides a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolydinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, Includes dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. The heterocyclyl group may be monocyclic or bicyclic. Unless otherwise stated, bicyclic heterocyclyl groups include, for example, chromanyl, 2,3-dihydrobenzo [b] [1,4] dioxynyl, tetrahydronaphthylidineyl, indolinyl, dihydropyrrolotriazolyl, imidazolypyrimidinyl, quinolinonyl. , Dioxaspirodecanyl, and other unsaturated heterocyclic radicals or unsaturated or saturated heterocyclic radicals fused to aromatic or heteroaryl rings. It will be appreciated that the attachment points of bicyclic heterocyclyl groups can be on heterocyclyl groups or aromatic rings that provide a stable structure. It will also be appreciated that if specified, any substituent on the heterocyclyl group may be present at any substitutable position, including, for example, the position to which the heterocyclyl binds.

The term "heteroaryl", used alone or as part of a larger portion such as "heteroarylalkyl," "heteroarylalkoxy," or "heteroarylaminoalkyl," refers to N, O, and S. A 5-10-membered aromatic radical containing 1 to 4 heteroatoms selected from, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, Includes thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indridinyl, prynyl, naphthidinyl, and pteridinyl. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". As used herein, the terms "heteroaryl" and "heteroaro" also include groups in which a heteroaromatic ring is fused to one or more aryl rings, with radicals or binding points on the heteroaromatic ring. .. Non-limiting examples include indrill, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, and quinoxalinyl. The heteroaryl group may be monocyclic or bicyclic. As specified, it will be appreciated that any substituent on the heteroaryl group can be present at any substitutable position, including, for example, the position to which the heteroaryl binds.

As used herein, the term "aryl", used alone or in combination with other terms, refers to a 6-14 member aromatic ring containing only a ring carbon atom. The aryl ring may be monocyclic, bicyclic, or tricyclic. Non-limiting examples include phenyl, naphthyl, biphenyl, anthracenyl and the like. It will also be appreciated that, if specified, any of the five substituents on the aryl group can be present at any substitutable position. In one embodiment, the aryl group is unsubstituted, mono- or di-substituted.

The terms "subject" and "patient" as used herein are interchangeable and require treatment for mammals such as companion animals (eg dogs, cats), livestock (eg cows, pigs, horses, etc.). Means sheep, goats, etc.) and laboratory animals (eg, rats, mice, guinea pigs, etc.). Usually, the subject is a human in need of treatment.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. For pharmaceutical use, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Pharmaceutically acceptable basic / cationic salts include sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine, and tri. Contains ethanolamine salts. Pharmaceutically acceptable acidic / anionic salts include, for example, acetates, benzenesulfonates, benzoates, bicarbonates, tartrates, carbonates, citrates, dihydrochlorides, gluconates, Glutamate, glycolyl alsanylate, hexylresolcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinic acid Includes salts, sulfates, tartrates, and tosylate.

All stereoisomers of the compound, including enantiomers and diastereomers, which may be present due to asymmetric carbons on various substituents, are within the scope of the invention. Conceivable. The individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (eg, as pure or substantially pure optical isomers with a particular activity), or. It may be mixed, for example, as a racemate or with all other, or other selected stereoisomers. The chiral center of the present invention may have an S or R configuration as defined by the International Pure Chemistry and Applied Chemistry Association (IUPAC) 1974 Recommendation. The racemate can be divided by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemate by any suitable method, including but not limited to conventional methods such as, for example, salt formation with an optically active acid followed by crystallization.

For example, if a particular enantiomer of the compounds of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture is separated and the auxiliary group Is cleaved to provide a purely desirable enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, a diastereomeric salt is formed with the appropriate optically active acid or base, followed by fractionated crystals or well known in the art. The chromatographic means of the above divides the formed diastereomers, resulting in the subsequent recovery of pure enantiomers.

It will be appreciated that the compounds described herein can be substituted with any number of substituents or functional moieties. In general, the term "substituted" with or without the term "arbitrarily", and the substituents contained in the formulas of the present invention are hydrogen radicals of a given structure with radicals of a particular substituent. Say the replacement of. When multiple positions of a given structure are substituted with multiple substituents selected from a particular group, the substituents may be the same or different at all positions. The term "substitution" as used herein is believed to include all acceptable substituents on organic compounds. In a broad sense, acceptable substituents include acyclic and cyclic, branched and non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have any acceptable substituents of the organic compounds described herein that satisfy the valences of hydrogen substituents and / or heteroatoms. ..

Furthermore, the invention is not intended to be limited in any way by the acceptable substituents of the organic compound. The combination of substituents and variables envisioned by the present invention preferably results in the formation of stable compounds useful, for example, in the treatment of neurodegenerative disorders. The term "stable" as used herein preferably has sufficient stability to enable production and is long enough to be detected, preferably detailed herein. Maintain the integrity of the compound for a sufficient period of time useful for the purpose.

またはその薬学的に許容し得る塩を提供し、ここで変数は上記の通りである。
第２の実施態様において、ｎが０、１または２である実施態様１の化合物が提供される。
第３の実施態様において、ｎが０、１、または２であり、ｐが２または３である、実施態様１の化合物が提供される。
第４の実施態様において、ＢおよびＹがＣＨである、実施態様３の化合物が提供される。
第５の実施態様において、Ｒ^２がシクロアルキル基である実施態様４の化合物が提供される。
第６の実施態様において、シクロアルキル基が５または６個の環炭素原子を有する実施態様５の化合物が提供される。
第７の実施態様において、Ｒ^２がアリール基である実施態様４の化合物が提供される。
第８の実施態様において、アリール基がフェニル基である、実施態様７の化合物が提供される。
第９の実施態様において、ｎが１または２である実施態様８の化合物が提供される。
第１０の実施態様において、Ｒ^５がハロゲンである、実施態様１〜９のいずれか１つの化合物が提供される。 3. 3. Description of Exemplary Compounds In the first embodiment, the present disclosure describes compounds of formula (I):

Or provide its pharmaceutically acceptable salt, where the variables are as described above.
In a second embodiment, the compound of embodiment 1 in which n is 0, 1 or 2 is provided.
In a third embodiment, the compound of embodiment 1 is provided, wherein n is 0, 1, or 2, and p is 2 or 3.
In a fourth embodiment, the compound of embodiment 3 is provided, wherein B and Y are CH.
In a fifth embodiment, the compound of embodiment 4 in which ^{R 2 is a cycloalkyl group is provided.}
In a sixth embodiment, the compound of embodiment 5 in which the cycloalkyl group has 5 or 6 ring carbon atoms is provided.
In a seventh embodiment, the compound of embodiment 4 in which ^{R 2 is an aryl group is provided.}
In an eighth embodiment, the compound of embodiment 7 in which the aryl group is a phenyl group is provided.
In a ninth embodiment, the compound of embodiment 8 in which n is 1 or 2 is provided.
In a tenth embodiment of, R ⁵ is halogen, a compound of any one of embodiments 1-9 is provided.

In a 11 embodiment of, R ¹ is a cycloalkyl group, a compound of any one of embodiments 1-9 is provided.
In a twelfth embodiment, the compound of embodiment 11 in which the cycloalkyl group is adamantane is provided.
In a 13 embodiment, the compound of any one of embodiments 1-9 thereof, wherein, R ¹ is an aryl group.
In a fourteenth embodiment, the compound of embodiment 13 in which the aryl group is a naphthyl group is provided.
In a 15 embodiment of the, R ⁴ is halogen, a compound of embodiment 13 is provided.
In a sixteenth embodiment, the compound of embodiment 13 is provided ^{, wherein R 1} is naphthyl and R ^{4 is halogen.}
In an embodiment of the 17, ^{R 4} is _C 1 -C ₆ alkoxy group, the compound of embodiment 13 is provided.
In a 18 embodiment of the, R ⁴ is a methoxy group, compounds of embodiment 17 is provided.
In an embodiment of the 19, R ¹ is an indazole group, a compound of any one of embodiments 1-9 is provided.
In a 20 embodiment, R ⁴ is an aryl group, the compound of embodiment 19 is provided.

In a twenty- ^first embodiment, any one of the compounds of embodiments 1-9, wherein R1 is an indole group, is provided.
In an embodiment of the 22, R ¹ is phenyl substituted aryl group, a compound of any one of embodiments 1-9 is provided.
In a 23 embodiment of, R ¹ is phenoxy substituted aryl group, a compound of any one of embodiments 1-9 is provided.
In a 24 embodiment of, R ¹ is a benzimidazole group, a compound of any one of embodiments 1-9 is provided.
In a 25th embodiment, any one compound of embodiments 1-9 is provided ^{, wherein R 3} is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} ..
In a 26th embodiment, the compound of embodiment 19 is provided ^{, wherein R 3} is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.}
In a 27th embodiment, the compound of embodiment 21 is provided, in the formula,
R ³ is H, R ⁴ is halogen or C _{1 to} C ₆ alkoxy, and R ⁵ is halogen.
In an embodiment of the 28, ^{R 3} is H, ^{R 4} is halogen or _C 1 -C ₆ alkoxy, ^{R 5} is halogen, compounds of embodiment 22 is provided.
In an embodiment of the 29, ^{R 3} is H, ^{R 4} is halogen or _C 1 -C ₆ alkoxy, ^{R 5} is halogen, compounds of embodiment 23 is provided.
In a 30 embodiment, ^{R 3} is H, ^{R 4} is halogen or _C 1 -C ₆ alkoxy, ^{R 5} is halogen, compounds of embodiment 24 is provided.

In a thirty-first embodiment, any one of the compounds of embodiments 1 to 3 is provided, wherein B is CH and Y is N.
In a 32 preferred embodiment, R ¹ is an aryl group, the compound of embodiment 31 is provided.
In a 33rd embodiment, the compound of embodiment 32, wherein the aryl group is naphthyl, is provided.
In a 34 embodiment of the, R ² is an aryl group, the compound of embodiment 33 is provided.
In a 35 embodiment of the, R ⁴ is halogen, a compound of embodiment 34 is provided.
In a 36 embodiment of, R ⁵ is halogen, compounds of embodiment 34 is provided.
In a thirty-seventh embodiment, the compound of embodiment 36, in which each of ^{R 4} and R ^{5 is a halogen, is provided.}
In a 38 embodiment of the, R ² is a cycloalkyl group, the compound of embodiment 31 is provided.
In a 39th embodiment, the compound of embodiment 38 is provided, wherein the cycloalkyl group has 5 or 6 ring carbon atoms.
In a 40th embodiment, the compound of embodiment 31 is provided, wherein X is O and R ¹ is a branched alkyl group of 5 carbons.

または薬学的に許容し得るその塩が提供される。
第４２の実施態様において、本開示は、実施態様１〜４１のいずれか１つによる化合物、またはその薬学的に許容し得る塩、および許容し得る担体を含む医薬組成物を提供する。
第４３の実施態様において、本開示は、対象のパーキンソン病を治療する方法を提供し、方法は、対象に実施態様１〜４１のいずれか１つに記載の、またはその薬学的に許容し得る１つの化合物の治療有効量を投与することを含む。
第４４の実施態様において、本開示は、脂質および非イオン性界面活性剤および当該化合物の薬理学的有効量の鼻吸収を可能にする促進剤の有効量の吸収と組み合わせた、実施態様１〜４１のいずれか１つに記載の化合物またはその薬学的に許容し得る塩を含む経鼻投与用の医薬組成物を提供する。
第４５の実施態様において、吸収促進剤がカチオン性ポリマーである、実施態様４４に記載の組成物が提供される。
第４６の実施態様において、カチオン性ポリマーがキトサンである、実施態様４５による組成物が提供される。
第４７の実施態様において、対象のパーキンソン病を治療する方法が提供され、この方法は、実施態様１〜４１のいずれか、またはその薬学的に許容される塩による化合物を含む経鼻投与用の治療有効量の医薬組成物を、脂質および非イオン性界面活性剤および薬理学的に有効な量の化合物の鼻吸収を可能にする有効量の吸収促進剤と組み合わせて、対象に投与することを含む。
第４８の実施態様において、吸収促進剤がカチオン性ポリマーである、実施態様４７による方法が提供される。
第４９の実施態様において、カチオン性ポリマーがキトサンである、実施態様４８による方法が提供される。
第５０の実施態様において、本開示は式（ＩＩ）

の化合物またはその薬学的に許容し得る塩を提供する。 In the 41st embodiment, a compound having a formula selected from the following;

Alternatively, the pharmaceutically acceptable salt is provided.
In a 42nd embodiment, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of embodiments 1-41 or a pharmaceutically acceptable salt thereof, and an acceptable carrier.
In a 43rd embodiment, the present disclosure provides a method of treating Parkinson's disease in a subject, wherein the method is described in any one of embodiments 1-41 or pharmaceutically acceptable thereof. It involves administering a therapeutically effective amount of one compound.
In a 44th embodiment, the present disclosure is combined with absorption of an effective amount of a lipid and a nonionic surfactant and an effective amount of a promoter that allows a pharmacologically effective amount of the compound to be absorbed nasally. Provided is a pharmaceutical composition for nasal administration, which comprises the compound according to any one of 41 or a pharmaceutically acceptable salt thereof.
In a 45th embodiment, the composition according to embodiment 44, wherein the absorption enhancer is a cationic polymer is provided.
In a 46th embodiment, the composition according to embodiment 45, wherein the cationic polymer is chitosan, is provided.
In a 47th embodiment, a method for treating Parkinson's disease of interest is provided, the method for nasal administration comprising a compound of any of embodiments 1-41 or a pharmaceutically acceptable salt thereof. A therapeutically effective amount of a pharmaceutical composition may be administered to a subject in combination with a lipid and nonionic surfactant and an effective amount of an absorption enhancer that allows nasal absorption of a pharmacologically effective amount of the compound. Including.
In a 48th embodiment, the method according to embodiment 47, wherein the absorption enhancer is a cationic polymer, is provided.
In a 49th embodiment, the method according to embodiment 48, wherein the cationic polymer is chitosan, is provided.
In the 50th embodiment, the present disclosure is in formula (II).

To provide a compound of or a pharmaceutically acceptable salt thereof.

In the 51st embodiment, the present disclosure provides the compound of the first embodiment, in which in formula 1, XY is C = C, m is 0 to 3, and R ₂ is a halogen. optionally substituted _{aryl, (C} 1 _{~C 6)} alkyl, halo _(C 1 _{~C 6) alkyl, (C} 1 _{~C 6)} alkoxy or halo _(C 1 _{~C 6)} alkoxy.
In a 52nd embodiment, the compound according to embodiment 51 is provided, where the aryl is phenyl optionally _{substituted with halogen, (C 1-} C ₆ ) alkyl, or halo (C _1- C ₆ ) alkyl. is there.
In a 53rd embodiment, the compound according to embodiment 50, wherein XY is C = C, m is 1, and R ₂ is (C _{2 to} C ₆ ) alkenyl or C _{2 to} C _{6) alkynyl.} Is provided.
In an embodiment of the 54, the present disclosure, _{R 2} is _(C 2 _{~C 6)} alkenyl, provides compounds of embodiment 53.
In a 55 embodiment of the, _{R 2} is _(C 2 _{~C 6)} alkynyl, Compounds according to embodiment 53 is provided.
In a 56th embodiment, the present disclosure provides a compound of embodiment 51, wherein _{R 3} is (C _1- C ₆ ) alkyl amino or di (C _1- C _{6) alkyl amino.}
In an embodiment of the 57 is _{R 3} is a di _(C 1 _{~C 6)} alkylamino, the compounds according to embodiment 56 is provided.
In a 58th embodiment, the present disclosure provides a compound of embodiment 57, wherein _{R 3} is N (CH ₃ ) _2.
In a 59th embodiment, the compound of embodiment 56, wherein _{R 2} is (C _1- C _{6) alkyl, is provided.}
In embodiment 51, in the 60th embodiment, m is 0 to 2, R ₃ is a halogen, and R ₂ is (C _{1 to} C ₆ ) alkyl or halo (C _{1 to} C ₆ ) alkyl. The compounds described are provided.

またはその薬学的に許容し得る塩が提供される。
第６９の実施態様において、本開示は、実施態様５０〜６８のいずれか１つに記載の化合物、その薬学的に許容し得る塩、および薬学的に許容し得る担体を含む医薬組成物を提供する。
第７０の実施態様において、対象のパーキンソン病を治療する方法が提供され、該方法は、対象に実施態様５０〜６８のいずれか１つに記載の化合物またはその薬学的に許容し得る塩の治療的有効量を投与することを含む。 In an embodiment of the 61, R ₁ is hydrogen, A compound according to embodiment 51 is provided.
In a 62 embodiment of the is phenyl R ₂ is optionally substituted with halogen A compound according to embodiment 61 is provided.
In an embodiment of the 63, R ₁ is hydrogen, Compounds according to embodiment 53 is provided.
In a 64 embodiment of the, _{R 2} is _(C 2 -C ₆₎ alkenyl, Compounds according to embodiment 63 is provided.
In a 65 embodiment of the compound according to embodiment 56 R ₁ is hydrogen is provided.
In an embodiment of the 66 is _{R 3} is a di _(C 1 _{~C 6)} alkylamino, Compounds according to embodiment 65 is provided.
In an embodiment of the 67, R ₁ is hydrogen, Compounds according to embodiment 60 is provided.
In the 68th embodiment, a compound having a formula selected from the following:

Alternatively, a pharmaceutically acceptable salt thereof is provided.
In a 69th embodiment, the present disclosure provides a pharmaceutical composition comprising the compound according to any one of embodiments 50-68, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. To do.
In the 70th embodiment, a method for treating Parkinson's disease of a subject is provided, the method of treating the subject with a compound according to any one of embodiments 50-68 or a pharmaceutically acceptable salt thereof. Includes administration of an effective amount.

In the 71st embodiment, the present disclosure is combined with an effective amount of a lipid and nonionic surfactant and an absorption enhancer that allows nasal absorption of a pharmacologically effective amount of the compound, embodiments 50-68. Provided is a pharmaceutical composition for nasal administration, which comprises a compound according to any one of the above or a pharmaceutically acceptable salt thereof.
In the 72nd embodiment, the composition according to the 71st embodiment, wherein the absorption enhancer is a cationic polymer is provided.
In a 73rd embodiment, the composition of embodiment 72, wherein the cationic polymer is chitosan, is provided.
In the 74th embodiment, the method of treating Parkinson's disease of interest is combined with an effective amount of a pharmacologically effective amount of lipid, nonionic surfactant and compound that allows nasal absorption of an absorption enhancer. It comprises administering to the subject a therapeutically effective amount of the compound according to any one of embodiments 50-68 or a pharmaceutically acceptable salt thereof.
In the 75th embodiment, the method of embodiment 74 is provided in which the absorption enhancer is a cationic polymer.
In the 76th embodiment, the method of embodiment 75, wherein the cationic polymer is chitosan, is provided.
In certain embodiments, the amount of compound represented by formula (I) or (II) in the provided composition is such that it is effective as a dual inhibitor of FKBP12 and FKBP52 in a biological sample or subject. Is. In certain embodiments, the provided compositions are formulated for administration to a subject in need of such a composition.
In some embodiments, the provided compositions are formulated for oral administration to a subject. In certain embodiments, the provided compositions are formulated for nasal administration to a subject.

4. Uses, formulations, and administration Pharmaceutically acceptable compositions:
The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not disrupt the pharmacological activity of the prescribed compound. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffers such as phosphates, Salts such as glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloid silica, magnesium trisilicate, etc. Alternatively, it includes, but is not limited to, electrolytes, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol, wool fat.

Remington's Pharmaceutical Sciences Ed. By Gennaro, Mack Publishing, Easton, Pa., 1995 (whose content is incorporated herein by reference) for the various carriers used in the formulation of pharmaceutical compositions and their preparation. It discloses known technology.

The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectal, nasal, buccal, vaginal, or via an implantable reservoir. As used herein, the term "parenteral" refers to subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrasubarachnoid, intrahepatic, intralesional, and intracranial injections or infusions. Technology is included.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms include, for example, water or ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly). Other solvents, solubilizers, and emulsifiers such as cotton seed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, esters of polyethylene glycol and fatty acid sorbitan, and mixtures thereof. Etc., which may include inert diluents commonly used in the art. In addition to the Inactive Diluent, the oral composition can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors, and flavors.

Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations are sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions of 1,3-butanediol. It may be. Among the acceptable vehicles and solvents that can be used are water, United States Pharmacopeia Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as solvents or suspension media. Any sterile fixed oil can be used for this purpose, including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable formulations. Injectable formulations are sterilized, for example, by filtration through a bacterial retention filter or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. be able to.

It is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection in order to prolong the effect of the compound provided. This can be achieved by using a liquid suspension of crystalline or amorphous material with low solubility in water. In that case, the absorption rate of the compound depends on its dissolution rate, and the dissolution rate may depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound form administered parenterally is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are created by forming a microcapsule matrix of compounds on a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled.
Examples of other biodegradable polymers include poly (orthoester) and poly (anhydride). Depot injection formulations are also prepared by enclosing the compound in liposomes or microemulsions that are compatible with body tissue.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compounds are sodium citrate or dicalcium phosphate, and / or (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and alginic acid, (b). Binding agents such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, acacia, (c) moisturizers such as glycerol, (d) agar, agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicic acid Salts and disintegrants such as sodium carbonate, (e) dissolution retarders such as paraffin, (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glycerol monostearate, ( h) At least one inert pharmaceutically at least one such as an absorbent such as kaolin and bentonite clay, and (i) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. It is mixed with an acceptable excipient or carrier. For capsules, tablets and pills, the dosage form may also include a buffer.

Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, and other coatings well known in the art of pharmaceutical formulations. They may optionally contain opalescent agents and may be compositions that release the active ingredient only in specific parts of the intestinal tract or, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

The compounds provided may also be in microencapsulated form with one or more of the above excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation technology. In such a solid dosage form, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also include additional substances other than the Inactive Diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is customary. For capsules, tablets and pills, the dosage form may also include a buffer. They may optionally contain opalescent agents and may be compositions that release the active ingredient only in specific parts of the intestinal tract, or preferentially, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and optionally the necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of the present invention.

Furthermore, the present invention anticipates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of compounds across the skin. The speed can be controlled by providing a speed control membrane or by dispersing the compound in a polymer matrix or gel.

The pharmaceutically acceptable compositions provided herein can be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.
The amount of compound provided that can be combined with the carrier material to produce a single dosage form composition will vary depending on the patient being treated and the particular mode of administration.

Specific doses and treatment plans for specific patients include age, weight, general health, gender, diet, duration of administration, excretion rate, drug combination, therapist's judgment, and the specific illness being treated. It should also be understood that it depends on various factors such as severity. The amount of compound provided in the composition will also depend on the compound in the composition.
Included within the scope of the invention is any of embodiments 1-41 or 50-68 described above in combination with an effective amount of absorption enhancer that allows a pharmacologically effective amount of the compound to be absorbed nasally. A pharmaceutical composition for nasal administration containing the compound according to the above or a pharmaceutically acceptable salt thereof.

Intranasal delivery is attractive as an alternative route for administration of drugs and biomolecules susceptible to enzymatic or acid degradation, first-pass hepatic metabolism, and to overcome the problem of low brain bioavailability due to the blood-brain barrier. The method. As such, the composition is useful in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as brain cancers such as glioblastoma, primary malignant brain tumors, and malignant glioma.

Nasal-administered drugs have the advantages of a relatively large surface area for penetration (provided by the large number of microvilli present in the nasal cavity), a porous intima, and access to highly angiogenic epithelium. .. Lipid and nonionic surfactant-based elastic vesicle delivery systems (eg, chitosan-based hybrid vesicle systems) that include agents that promote absorption into the mucous membrane are conventional dosage forms (solutions, suspensions, Shows enhanced permeability compared to sprays, snuffs, emulsions, and gels). These vesicle delivery systems contain both stabilizing and destabilizing molecules within a single bilayer wall, providing elasticity and also allowing the system to act as a barrier regulator. Intranasal routes have proven to be promising means for using these delivery systems, allowing close and long-term contact between drug carriers and mucosa. In addition to improved permeability, the vesicles of lipid and nonionic surfactant-based elastic vesicle delivery systems are highly stable and have a high capacity for drug loading and controlled release profiles, all of which Taken into account, they are a good choice as carriers for both hydrophilic and lipophilic drug molecules.

Absorption enhancers that may be used in the nasal compositions described herein include cationic polymers, surfactants, chelating agents, mucolytic agents, cyclodextrins, and combinations thereof. .. In addition, the cationic polymers that can be used include inorganic or organic salts of chitosan and other polycationic carbohydrates such as modified forms of chitosan (particularly more positively charged), polyamino acids such as polylysine, polyquaternary compounds. , Protamine, polyamine, DEAE-imine, polyvinylpyridine, polythiodiethyl-aminomethylethylene (P (TDAE)), polyhistidine, DEAE-methacrylate, DEAE-acrylamide, poly-p-aminostyrene, polyoxetane, copolymethacrylate ( HPMA, N- (2-hydroxypropyl) methacrylicamide copolymers, etc.), GAFQUAT (US Pat. No. 3,910,862), polyamide amines, etc. are included. The polycationic material used in the present invention typically has a molecular weight of 10,000 or more. Chitosan (or a salt thereof) preferably has an intrinsic viscosity of at least 400 ml / g, more preferably at least 500, 750 or 1000 ml / g.

5. Use of Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein potent in the formation of a-SYN aggregates present in Lewy bodies (LBs) that are characteristic of the pathology of Parkinson's disease. It is generally useful for double inhibition of FKBP12 and FKBP52, which promotes. Therefore, in some embodiments, the present disclosure provides a method of treating Parkinson's disease, comprising administering the provided compound or composition.

As used herein, the terms "treat," "treat," and "treat ~" reverse or alleviate the progression of a disease or disorder, or one or more of the symptoms described herein. It refers to delaying or inhibiting the start. In some embodiments, treatment, i.e., therapeutic treatment, can be given after the appearance of one or more symptoms. In other embodiments, treatment may be given in the absence of symptoms. For example, a sensitive individual can be treated, i.e. prophylactically, prior to the onset of symptoms (eg, in the light of a history of symptoms and / or in the light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have subsided, for example to prevent or delay recurrence.

The present disclosure further provides methods of treating subjects such as humans suffering from Parkinson's disease.
The disclosure further relates to the use of compounds provided for the manufacture of pharmaceutical compositions used in the treatment and / or prevention and / or amelioration of Parkinson's disease.

The compounds or compositions described herein can be administered using any amount and route of administration that is effective in treating or alleviating the severity of Parkinson's disease. The exact amount required will vary from subject to subject, depending on the species, age, and general symptoms of the subject, the severity of the disease, the particular drug, the mode of administration thereof, and the like. The compounds provided are preferably formulated in unit dose form for ease of administration and dose uniformity.

As used herein, the expression "unit dosage form" refers to a physically separate unit of drug appropriate for the patient being treated. However, it will be appreciated that the total daily use of the compounds and compositions of the present disclosure will be determined by the attending physician within sound medical judgment. Specific effective dose levels for a particular patient or organism are the disorder during treatment and the severity of the disorder, the activity of the particular compound used; the particular composition adopted; the patient's age, weight, general health. , Gender, and diet; time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination with or at the same time as the particular compound used, and well known in the medical field. It depends on a variety of factors, including similar factors that have been identified.

The pharmaceutically acceptable compositions of the present disclosure are oral, rectal, parenteral, intracapsular, intravaginal, intraperitoneal, topical (powder,) to humans and other animals, depending on the severity of the infection being treated. It can be administered as an ointment, or as a drop), cheek, oral or nasal spray. In certain embodiments, the compounds provided are about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg body weight / day of the subject in order to obtain the desired therapeutic effect. It may be administered orally or parenterally multiple times daily at dose levels.

As used herein, the term "biological sample" refers to cell cultures or extracts thereof, biopsy materials obtained from mammals or extracts thereof, and blood, saliva, urine, feces, semen, tears. , Or other body fluids or extracts thereof, but not limited to these.

Both amounts of the provided compounds and additional therapeutic agents (these compositions comprising the additional therapeutic agents described above) that can be combined with the carrier material to produce a single dosage form are the host to be treated and Depends on the particular mode of administration.

In these compositions comprising an additional therapeutic agent, the additional therapeutic agent and the provided compound may act synergistically. Therefore, the amount of additional therapeutic agent in such a composition will be less than the amount required for monotherapy using only that therapeutic agent. The amount of additional therapeutic agent present in the compositions of the present disclosure is less than or equal to the amount normally administered in a composition comprising the therapeutic agent as the sole active agent.

In certain exemplary embodiments, the compounds are prepared according to the following general procedures, as shown in the examples below. Although general methods indicate the synthesis of specific compounds of the invention, the following general methods, and other methods known to those of skill in the art, are all compounds and these compounds described herein. It will be appreciated that it can be applied to each subclass and species of.

General:
Unless otherwise stated, all anhydrous solvents were commercially available and stored in Sure-seal bottles under nitrogen. All other reagents and solvents were purchased as the highest grade available and used without further purification. Thin layer chromatography (TLC) analysis of the reaction mixture was performed using a Merck silica gel 60 F254 TLC plate and visualized using ultraviolet light. The NMR spectrum was recorded on a Bruker 500 MHz instrument. Chemical shifts (S) are reported in parts per million (ppm) ^{relative to 1} H (Me _{4 Si at 0.00).} The coupling constant (J) is consistently reported in Hz. Mass spectrometric data were obtained by Shimadzu LCMS-2010EV for low resolution and Agilent ESI-TOF for high or low resolution. Purity of all compounds was obtained by HPLC Breeze from Waters Co. using an Atlantis T 33 μm 4.6x150 mm reversed phase column. The eluate had a linear gradient from 95% A and 5% B to 5% A and 95% B at a flow rate of 1 ml / min for 15 minutes, followed by 100% B for 5 minutes (solvent A:). H ₂ O containing 0.1% TFA; Solvent B: Acetonitrile containing 0.1% TFA). The compound was detected at λ = 254 nm or 214 nm. The purity of the major compounds was established by elemental analysis performed on the Perkin Elmer Series II-2400. Combustion analysis was performed by NuMega Resonance Labs in San Diego, California, USA.

Synthesis:
The compound according to the formula (I) can be prepared by a technique recognized in the art. Shown in Examples 1-14 below are the structures of 14 exemplary compounds of formula (I) and methods of their preparation. Analytical data for the compounds thus prepared are also described in Examples 1-14, and procedures for testing these compounds are described in Examples 15-17 below.

試薬と条件：（ａ）ＨＣｌ、１２５〜１３０℃、エチレングリコール、４時間；（ｂ）４−メチルベンジルクロリド、Ｋ_２ＣＯ_３、ＤＭＦ、１１０℃、６時間。 Compounds according to formula (II) can be prepared by techniques recognized in the art using the following synthetic schemes:
Scheme 1

Reagents and conditions: (a) HCl, 125~130 ℃ , ethylene glycol, 4 h; (b) 4-methylbenzyl _{chloride, K 2 CO 3, DMF,} 110 ℃, 6 hours.

試薬と条件：（ａ）Ｅｔ_３Ｎ、Ｂｏｃ−無水物、ＣＨ_３ＣＮ、室温、１６時間。（ｂ）Ｐｄ（Ｐｈ_３Ｐ）_２Ｃｌ_２、Ｃｕｌ、Ｅｔ_３Ｎ、ＣＨ_３ＣＮ、７８℃、１６時間；（ｃ）ＴＦＡ、ＤＣＭ、室温、３時間；（ｄ）Ｒ_１−Ｂｒ、Ｋ_２Ｃ０_３、ＤＭＦ、１１０℃、８時間。 Scheme 2:

Reagents and conditions: (a) Et ₃ N, Boc-anhydride, CH ₃ CN, room temperature, 16 hours. (B) Pd (Ph ₃ P) ₂ Cl ₂ , Cul, Et ₃ N, CH ₃ CN, 78 ° C., 16 hours; (c) TFA, DCM, room temperature, 3 hours; (d) R _1- Br, K _{2 C0 3, DMF, 110 ℃} , 8 hours.

試薬と条件：（ａ）ＨＣｌ、エチレングリコール、１２５〜１３０℃；（ｂ）４−メチルベンジルクロリド、Ｋ_２ＣＯ_３、ＤＭＦ、１１０℃。 Scheme 3:

Reagents and conditions: (a) HCl, ethylene glycol, 125~130 ℃; (b) 4- methylbenzyl _{chloride, K 2 CO 3, DMF,} 110 ℃.

試薬と条件：（ａ）、ＮａＮＯ_２、ＨＣｌ、０℃、次にＮａ_２ＣＯ_３、ベンズイミダゾール誘導体。（Ｂ）ＮａＨ、Ｒ_１０−Ｉ、ＴＨＦ。
Ｒ_１、Ｒ_２、Ｒ_３、Ｒ_４、Ｒ_５、Ｒ_６、Ｒ_７、Ｒ_８、Ｒ_９は、独立して、例えば、Ｈ、（Ｃ_１−Ｃ_６）アルキル、例えばＭｅ、Ｅｔ；（（Ｃ_１−Ｃ_６）アルコキシ、例えばＯＭｅ、ＯＥｔ、またはハロゲン化物のいずれかであり得る。。Ｒ_１０は、例えば、（Ｃ_１−Ｃ_６）アルキル、例えば、Ｍｅ、Ｅｔ、ｎ−プロピル、およびイソプロピルであり、または（Ｃ_３−Ｃ_１０）シクロアルキル、例えばシクロプロパン、シクロブタン、シクロペンタン、およびシクロヘキサンである。
実施例１８〜１９は、式（ＩＩ）の２つの例示的な化合物の構造およびそれらの調製方法である。このように調製された化合物の分析データも実施例１８〜１９に記載されており、これらの化合物を試験する手順は以下の実施例２０〜２２に記載されている。 Scheme 4:

Reagents and conditions: (a), NaNO ₂ , HCl, 0 ° C, then Na ₂ CO ₃ , benzimidazole derivative. (B) NaH, R _10- I, THF.
R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ independently, for example, H, (C _1- C ₆ ) alkyl, for example Me, Et; _((C 1 -C ₆₎ alkoxy, for example OMe, OEt or _{..R 10} which may be either a halide, is, for _{example, (C} 1 -C ₆₎ alkyl, e.g., Me, Et, n-propyl , And isopropyl, or (C _3- C ₁₀ ) cycloalkyls, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
Examples 18-19 are the structures of two exemplary compounds of formula (II) and methods of their preparation. Analytical data for the compounds thus prepared are also described in Examples 18-19, and procedures for testing these compounds are described in Examples 20-22 below.

ＣＡＰ０１６８７を作成するための以下に示す合成スキーム（スキーム４）は、式（Ｉ）のすべての化合物の合成の例である。

Synthesis of (2S) -3- (4-chlorophenyl) -2-[(6-fluoronaphthalene-2-yl) -formamide-N- (3-phenylpropyl) propanamide (CAP01687; compound 4))

The synthetic scheme shown below (Scheme 4) for making CAP01687 is an example of the synthesis of all compounds of formula (I).

Intermediate compound 2, tert-butyl N [(1S) -2 (4-chlorophenyl) -1-[(3-phenyl) carbamoyl] ethyl] Carbamate synthesis Boc-L-4-chlorophenylalanine (923 mg, 3.08 mmol) , 3-Phenylpropylamine (417 mg, 3.08 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC; 705 mg, 3.69 mmol), hydroxybenzotriazole (HOBt; 498 mg, 3.69 mmol). 69 mmol), and N, N-diisopropylethylamine (DIEA; 1.33 mL, 7.70 mmol) in DMF (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO ₃ solution (100 mlx3), brine (100 mlx3), dried with sulfonyl ₄ and filtered. The organic layer was concentrated on a rotary evaporator and the residue was purified by silica gel column chromatography using hexane-ethyl acetate to give compound 2 (960 mg, 75%).
^{1 1} HNMR (500 MHz, DMSO-de) δ 1.30 (s, 9 H), 1.62-1.67 (m, 2 H), 2.51-2.54 (, 2 H), 2.71-2.74 (m, 1 H), 2.88- 2.99 (m, 1 H), 3.02-3.07 (m, 2 H), 4.01 -4.12 (m, 1 H), 6.91 (d, J = 9 Hz, 1 H), 7.15-7.19 (m, 3 H) , 7.25-7.29 (m, 4 H), 7.31 (d, J = 8 Hz, 2 H), 7.91 (t, J = 5 Hz, 1 H, NH); ESI-MS m / z 439 (M + Na) ) +, 417 (M + H) +.

Synthesis of Intermediate Compound 3, (2S) -2-amino-3 (4-chlorophenyl) -N- (3-phenylpropyl) -propanamide (Compound 3)
A solution of compound 2 (48 mg, 0.11 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuum and dried in a vacuum pump. This compound was used in the next step without further purification.

Synthesis of final compound 4 Compound 3 (36 mg, 0.11 mmol), 6-fluoro-2-naphthoic acid (22 mg, 0.11 mmol), EDC (26 mg, 0.13 mmol), HOBt (19 mg, 0.13 mmol) , DIEA (0.1 mL, 0.57 mmol) in DMF (2 mL) was stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate (100 mL), washed with saturated NaHCO ₃ solution (3x100 mL), brine (3x100 mL), dried (sulfonyl ₄ ) and concentrated in vacuo. The residue was purified on a silica gel column using a hexane-ethyl acetate system to provide compound 4 (37 mg, 70%).
^{1 1} HNMR (500 MHz, DMSO-de) δ 1.66-1.72 (m, 2 H), 2.53-2.57 (m, 2 H), 3.01 -3.14 (, 4 H), 4.71-4.76 (m, 1 H), 7.14-7.18 (m, 3 H), 7.23-7.28 (m, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.48-7.52 ( m, 1 H), 7.75-7.78 (m, 1 H), 7.93-7.97 (m, 2 H), 8.01 -8.12 (m, 1 H), 8.15 (t, J = 5.5 Hz, 1 H, NH) , 8.47 (s, 1 H), 8.74 (d, J = 8.5 Hz, 1 H); ESI-MS m / z 511 (M + Na) +, 489 (M + H) +.
According to the above procedure, other compounds were synthesized using suitable chemicals and reagents as shown in Scheme 4.

¹HNMR (500 MHz, DMSO-d6) δ 1.06-1.26 (m, 7 H), 1.62-1.83 (m, 6 H), 2.61 (t, J = 5.6 Hz, 2 H), 3.09-3.19 (m, 2 H), 4.35-4.39 (m, 1 H), 7.16-7.29 (m, 5 H), 7.47-7.60 (m, 4 H), 7.95 (d, J = 8 Hz, 1 H), 8.00 (d, J = 8 Hz, 1 H), 8.12 (t, J = 5.6 Hz, 1 H, NH), 8.16 (d, J = 8.5 Hz, 1 H), 8.45 (d, J = 8 Hz, 1 H); ESI-MS m/z 451 (M+Na)+, 429 (M+H)+. (2S) -2-Cyclohexyl-2- (naphthalene-1-ylformamide) -N- (3-phenylpropyl) acetamide (CAP01678):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.06-1.26 (m, 7 H), 1.62-1.83 (m, 6 H), 2.61 (t, J = 5.6 Hz, 2 H), 3.09-3.19 (m, 2 H), 4.35-4.39 (m, 1 H), 7.16-7.29 (m, 5 H), 7.47-7.60 (m, 4 H), 7.95 (d, J = 8 Hz, 1 H), 8.00 (d , J = 8 Hz, 1 H), 8.12 (t, J = 5.6 Hz, 1 H, NH), 8.16 (d, J = 8.5 Hz, 1 H), 8.45 (d, J = 8 Hz, 1 H) ESI-MS m / z 451 (M + Na) +, 429 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.71 -1.77 (m, 2 H), 2.60 (t, J = 6.5 Hz, 2 H), 2.88-2.91 (m, 1 H), 3.01 -3.16 (m, 3 H), 4.9-4.84 (m, 1 H), 7.16-7.29 (m, 5 H), 7.31 -7.42 (m, 5 H), 7.47-7.53 (m, 3 H), 7.76 (d, J =8.5 Hz, 1 H), 7.93 (d, J= 9 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 8.15 (t, J = 5.6 Hz, 1H, NH), 8.70 (d, J = 8.5 Hz, 1 H); ESI-MS m/z 493 (M+Na)+, 471 (M+H)+. (2S) -2- (adamantane-1-yl) formamide-2-cyclohexyl-N- (3-phenylpropyl) acetamide (CAP01680)

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.71 -1.77 (m, 2 H), 2.60 (t, J = 6.5 Hz, 2 H), 2.88-2.91 (m, 1 H), 3.01 -3.16 (m, 3 H), 4.9-4.84 (m, 1 H), 7.16-7.29 (m, 5 H), 7.31 -7.42 (m, 5 H), 7.47-7.53 (m, 3 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 9 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 8.15 (t, J = 5.6 Hz, 1H, NH), 8.70 (d , J = 8.5 Hz, 1 H); ESI-MS m / z 493 (M + Na) +, 471 (M + H) +.

1HNMR (500 MHz, DMSO-d6) δ 1.71 -1.77 (m, 2 H), 2.60 (t, J = 6.5 Hz, 2 H), 2.88-2.91 (m, 1 H), 3.01 -3.16 (m, 3 H), 4.9-4.84 (m, 1 H), 7.16-7.29 (m, 5 H), 7.31 -7.42 (m, 5 H), 7.47-7.53 (m, 3 H), 7.76 (d, J =8.5 Hz, 1 H), 7.93 (d, J= 9 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 8.15 (t, J = 5.6 Hz, 1H, NH), 8.70 (d, J = 8.5 Hz, 1 H); ESI-MS m/z 493 (M+Na)+, 471 (M+H)+. (2S) -3- (4-chlorophenyl) -2- (naphthalene-1-ylformamide) -N- (3-phenylpropylpropanamide (CAP 01681)):

1HNMR (500 MHz, DMSO-d6) δ 1.71 -1.77 (m, 2 H), 2.60 (t, J = 6.5 Hz, 2 H), 2.88-2.91 (m, 1 H), 3.01 -3.16 (m, 3) H), 4.9-4.84 (m, 1 H), 7.16-7.29 (m, 5 H), 7.31 -7.42 (m, 5 H), 7.47-7.53 (m, 3 H), 7.76 (d, J = 8.5) Hz, 1 H), 7.93 (d, J = 9 Hz, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 8.15 (t, J = 5.6 Hz, 1H, NH), 8.70 (d, J = 8.5 Hz, 1 H); ESI-MS m / z 493 (M + Na) +, 471 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.66-1.72 (, 2 H), 2.54 (t, J = 5.6 Hz, 2 H), 3.01-3.14 (m, 4 H), 4.71 -4.76 (m, 1 H), 7.14-7.19 (m, 3 H), 7.23-7.28 (m, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.57-7.62 (m, 2 H), 7.88-8.01 (m, 4 H), 8.15 (t, J =5.6 Hz, 1 H, NH), 8.43 (d, J = 1.1 Hz, 1 H), 8.74 (d, J = 5.6 Hz, 1 H, NH); ESI-MS m/z 493 (M+Na)+, 471 (M+H)+. (2S) -3- (4-chlorophenyl) -2- (naphthalene-2-ylformamide) -N- (3-phenylpropylpropanamide (CAP01684)):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.66-1.72 (, 2 H), 2.54 (t, J = 5.6 Hz, 2 H), 3.01-3.14 (m, 4 H), 4.71 -4.76 (m, 1) H), 7.14-7.19 (m, 3 H), 7.23-7.28 (m, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.57 -7.62 (m, 2 H), 7.88-8.01 (m, 4 H), 8.15 (t, J = 5.6 Hz, 1 H, NH), 8.43 (d, J = 1.1 Hz, 1 H), 8.74 (d , J = 5.6 Hz, 1 H, NH); ESI-MS m / z 493 (M + Na) +, 471 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.57-1.68 (m, 15 H), 1.90-1.92 (m, 3 H), 2.52 (t, J = 6.2 Hz, 2 H), 2.86-3.09 (m, 4 H), 4.43-4.48 (m, 1 H), 7.14-7.32 (m, 10 H), 7.88 (t, J = 5.7 Hz, 1 H, NH); ESI-MS m/z 502 (M+Na)+, 480 (M+H)+. (2S) -2- (adamantane-1-ylformamide) -3- (4-chlorophenyl) -N- (3-phenylpropyl) propanamide (CAP01 685):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.57-1.68 (m, 15 H), 1.90-1.92 (m, 3 H), 2.52 (t, J = 6.2 Hz, 2 H), 2.86-3.09 (m, 4 H), 4.43-4.48 (m, 1 H), 7.14-7.32 (m, 10 H), 7.88 (t, J = 5.7 Hz, 1 H, NH); ESI-MS m / z 502 (M + Na) ) +, 480 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.66-1.71 (m, 2 H), 2.54 (t, J = 6.5 Hz, 2 H), 2.98-3.14 (m, 4 H), 4.72-4.78 (m, 1 H), 7.14-7.39 (m, 9 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.86 (t, J = 7.5 Hz, 1 H), 8.08 (t, J = 7.6 Hz, 2 H), 8.19 (t, J = 6.3 Hz, IH, NH), 8.80 (s, 1 H), 9.00 (d, J = 6.2 Hz, 1 H, NH), 9.21 (s, 1 H); ESI-MS m/z 494 (M+Na)+, 472 (M+H)+. (2S) -3- (4-chlorophenyl) -N- (3-phenylpropyl) -2- (quinoline-3-yl) formamide propanamide (CAP01 686):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.66-1.71 (m, 2 H), 2.54 (t, J = 6.5 Hz, 2 H), 2.98-3.14 (m, 4 H), 4.72-4.78 (m, 1 H), 7.14-7.39 (m, 9 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.86 (t, J = 7.5 Hz, 1 H), 8.08 (t, J = 7.6 Hz, 2) H), 8.19 (t, J = 6.3 Hz, IH, NH), 8.80 (s, 1 H), 9.00 (d, J = 6.2 Hz, 1 H, NH), 9.21 (s, 1 H); ESI- MS m / z 494 (M + Na) +, 472 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.66-1.72 (m, 2 H), 2.55 (t, J = 7 Hz, 2 H), 3.00-3.12 (m, 4 H), 4.67-4.72 (m, 1 H), 7.14-7.19 (m, 3 H), 7.24-7.28 (m, 2 H), 7.31 (d, J = 8 Hz, 2 H), 7.37 (d, J = 8 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 8.03 (s, 1 H), 8.12-8.14 (m, 2 H), 8.69 (d, J = 8 Hz, 1 H), 13.35 (br s, 1 H, NH); ESI-MS m/z 483 (M+Na)+, 461 (M+H)+. (2S) -3- (4-chlorophenyl) -2- (1H-indazole-6-ylformamide) -N- (3-phenylpropyl) propanamide (CAP 01688):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.66-1.72 (m, 2 H), 2.55 (t, J = 7 Hz, 2 H), 3.00-3.12 (m, 4 H), 4.67-4.72 (m, 1 H), 7.14-7.19 (m, 3 H), 7.24-7.28 (m, 2 H), 7.31 (d, J = 8 Hz, 2 H), 7.37 (d, J = 8 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 8.03 (s, 1 H), 8.12-8.14 (m, 2 H), 8.69 (d, J = 8 Hz, 1 H), 13.35 (br s, 1 H, NH); ESI-MS m / z 483 (M + Na) +, 461 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.68-1.71 (m, 2 H), 2.55 (t, J = 5.6 Hz, 2 H), 3.01 -3.14 (m, 4 H), 4.70-4.74 (m, 1 H), 7.31 -7.38 (m, 5 H), 7.50 (t, J = 8 Hz, 1 H), 7.61 (d, J = 8 Hz, 1 H), 7.76 (d, J = 8 Hz, 1 H), 7.92-7.98 (m, 2 H), 8.1 1 (t, J = 8 Hz, 1 H), 8.18 (t, J = 5.4 Hz, 1 H, NH), 8.40-8.48 (m, 3 H), 8.75 (d, J = 8 Hz, 1 H); ESI-MS m/z 512 (M+Na)+, 490 (M+H)+. (2S) -3- (4-chlorophenyl) -2-[(6-fluoronaphthalene-2-yl) -formamide] N- [3- (pyridin-3-yl) propylpropanamide (CAP01 693):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.68-1.71 (m, 2 H), 2.55 (t, J = 5.6 Hz, 2 H), 3.01 -3.14 (m, 4 H), 4.70-4.74 (m, 1 H), 7.31 -7.38 (m, 5 H), 7.50 (t, J = 8 Hz, 1 H), 7.61 (d, J = 8 Hz, 1 H), 7.76 (d, J = 8 Hz, 1) H), 7.92-7.98 (m, 2 H), 8.1 1 (t, J = 8 Hz, 1 H), 8.18 (t, J = 5.4 Hz, 1 H, NH), 8.40-8.48 (m, 3 H) ), 8.75 (d, J = 8 Hz, 1 H); ESI-MS m / z 512 (M + Na) +, 490 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.67-1.73 (m, 2 H), 2.55 (t, J = 5.6 Hz, 2 H), 3.02-3.14 (m, 4 H), 4.69-4.74 (m, 1 H), 7.15-7.19 (m, 3 H), 7.25-7.32 (m, 4 H), 7.38-7.43 (m, 3 H), 7.53 (t, J = 8 Hz, 2 H), 7.65 (dd, J = 8 and 1.2 Hz, 1 H), 8.00 (d, J = 7 Hz, 2H), 8.07-8.11 (m, 2 H), 8.16 (t, J = 5.6 Hz, 1 Η,ΝΗ), 8.78 (d, J = 8.5 Hz, 1 H), 13.54 (br s, 1 H, NH); ESI-MS m/z 560 (M+Na)+, 538 (M+H)+. (2S) -3- (4-chlorophenyl) -2-[(3-phenyl-1H indazole-6-yl) formamide] -N- (3-phenylpropyl) propanamide (CAP01717):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.67-1.73 (m, 2 H), 2.55 (t, J = 5.6 Hz, 2 H), 3.02-3.14 (m, 4 H), 4.69-4.74 (m, 1 H), 7.15-7.19 (m, 3 H), 7.25-7.32 (m, 4 H), 7.38-7.43 (m, 3 H), 7.53 (t, J = 8 Hz, 2 H), 7.65 (dd , J = 8 and 1.2 Hz, 1 H), 8.00 (d, J = 7 Hz, 2H), 8.07-8.11 (m, 2 H), 8.16 (t, J = 5.6 Hz, 1 Η, ΝΗ), 8.78 (d, J = 8.5 Hz, 1 H), 13.54 (br s, 1 H, NH); ESI-MS m / z 560 (M + Na) +, 538 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.67-1.72 (m, 2 H), 2.55 (t, J = 5.4 Hz, 2 H), 3.02-3.14 (m, 4 H), 4.71 -4.75 (m, 1 H), 7.14-7.19 (m, 3 H), 7.24-7.34 (m, 8 H), 7.50 (d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 1 H), 8.19 (t, J = 5.6 Hz, 1 H, NH), 8.68 (d, J = 8.5 Hz, 1 H, NH), 13.20 (br s, 1 H, NH); ESI-MS m/z 483 (M+Na)+, 461 (M+H)+. (2S) -2- (1H-1,3-benzodiazole-2-ylformamide) -3- (4-chlorophenyl) -N- (3-phenylpropyl) propanamide (CAP01721):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.67-1.72 (m, 2 H), 2.55 (t, J = 5.4 Hz, 2 H), 3.02-3.14 (m, 4 H), 4.71 -4.75 (m, 1 H), 7.14-7.19 (m, 3 H), 7.24-7.34 (m, 8 H), 7.50 (d, J = 8 Hz, 1H), 7.74 (d, J = 8 Hz, 1 H), 8.19 (t, J = 5.6 Hz, 1 H, NH), 8.68 (d, J = 8.5 Hz, 1 H, NH), 13.20 (br s, 1 H, NH); ESI-MS m / z 483 (M +) Na) +, 461 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.65-1.71 (m, 2 H), 2.54 (t, J = 5.6 Hz, 2 H), 3.01 - 3.12 (m, 4 H), 4.73-4.78 (m, 1 H), 7.1 1 -7.29 (m, 10 H), 7.41 (t, J = 8 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 8.01 -8.14 (m, 2 H), 8.20 (t, J = 5.4 Hz, 1 H, NH), 13.66 (br s, 1 H, NH); ESI-MS m/z 483 (M+Na)+, 461 (M+H)+. (2S) -3- (4-chlorophenyl) -2- (1H indazole-3-ylformamide) -N- (3-phenylpropyl) propanamide (CAP01722):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.65-1.71 (m, 2 H), 2.54 (t, J = 5.6 Hz, 2 H), 3.01 --3.12 (m, 4 H), 4.73-4.78 (m, 1 H), 7.1 1 -7.29 (m, 10 H), 7.41 (t, J = 8 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 8.01 -8.14 (m, 2 H) , 8.20 (t, J = 5.4 Hz, 1 H, NH), 13.66 (br s, 1 H, NH); ESI-MS m / z 483 (M + Na) +, 461 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.65-1.71 (m, 2 H), 2.47-2.51 (m, 2 H), 3.08-3.14 (m, 2 H), 5.73 (d, J = 7 Hz, 1 H), 7.10-7.25 (m, 3 H), 7.31 -7.57 (m, 8 H), 7.78 (dd, J = 8 and 1.4 Hz, 1 H), 7.96=8.03 (m, 2 H), 8.12-8.15 (m, 1 H), 8.37 (t, J = 5.6 Hz, 1 H, NH), 8.62 (s, 1 H), 8.92 (d, J = 8 Hz, 1 H); ESI-MS m/z 463 (M+Na)+, 441 (M+H)+. (2S) -2-[(6-Fluoronaphthalene-2-yl) formamide] -2-phenyl-N- (3-phenylpropyl) acetamide (CAP01723):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.65-1.71 (m, 2 H), 2.47-2.51 (m, 2 H), 3.08-3.14 (m, 2 H), 5.73 (d, J = 7 Hz, 1 H), 7.10-7.25 (m, 3 H), 7.31 -7.57 (m, 8 H), 7.78 (dd, J = 8 and 1.4 Hz, 1 H), 7.96 = 8.03 (m, 2 H), 8.12 -8.15 (m, 1 H), 8.37 (t, J = 5.6 Hz, 1 H, NH), 8.62 (s, 1 H), 8.92 (d, J = 8 Hz, 1 H); ESI-MS m / z 463 (M + Na) +, 441 (M + H) +.

¹HNMR (500 MHz, DMSO-d6) δ 1.68-1.72 (m, 2 H), 2.52-2.54 (m, 2 H), 3.10-3.12 (m, 2 H), 5.74 (d, J = 7 Hz, 1 H), 7.27-7.28 (m, 1 H), 7.44-7.60 (m, 6 H), 7.78 (d, J = 5 Hz, 1 H), 7.96-8.03 (m, 2 H), 8.1 1 -8.14 (m, 1 H), 8.42-8.44 (m, 2 H), 8.62 (s, 1 H), 9.01 (d, J = 8 Hz, 1 H); ESI-MS m/z 498 (M+Na)+, 476 (M+H)+. (2S) -2- (4-chlorophenyl) -2-[(6-fluoronaphthalene-2-yl) formamide] N- [3-pyridin-3-yl) propyl] acetamide (SKD-II-13):

^{1 1} HNMR (500 MHz, DMSO-d6) δ 1.68-1.72 (m, 2 H), 2.52-2.54 (m, 2 H), 3.10-3.12 (m, 2 H), 5.74 (d, J = 7 Hz, 1 H), 7.27-7.28 (m, 1 H), 7.44-7.60 (m, 6 H), 7.78 (d, J = 5 Hz, 1 H), 7.96-8.03 (m, 2 H), 8.1 1- 8.14 (m, 1 H), 8.42-8.44 (m, 2 H), 8.62 (s, 1 H), 9.01 (d, J = 8 Hz, 1 H); ESI-MS m / z 498 (M + Na) ) +, 476 (M + H) +.

Ki putative ligand binding was measured by fluorescein isothiocyanate (FITC) labeled probe fluorescently polarized light (described in Bollini et al 2002) in combination with the recombinant full length FKBP12 and FKBP52.
A binding saturation experiment was performed to determine the probe Kd of FKBP12 or FKBP52 using GraphPad software. Ligand substitution from FKBP12 or FKBP52 was measured by fluorescence polarization in the presence of various compound concentrations. Using GraphPad software to determine the IC ₅₀ for each compound. Nikolovska-Coleska, using the formulas described et al 2004, it was estimated Ki using IC ₅₀ values for each compound. See Table 1 below.

Neuroprotective BE (2) -M17 human neuroblastoma cells stably express either wild-type or A53T mutant a-sinucrane, PC12 rat chromaffin cell tumor, or SH-SY5Y human neuroblastoma cells. And were cultured in 96-well cell culture dishes in a humidified incubator under 37 ° C. and 5% CO _2. Growth medium was supplemented with 0.1% dimethyl sulfoxide (vehicle control) or a compound dissolved in dimethyl sulfoxide.

After 2 hours of exposure to the compound, the growth medium was further supplemented with 6-hydroxydopamine (or 0.1% ascorbic acid vehicle control) and incubated for an additional 24-48 hours. Cell viability was measured by reduction of WST-8 or AramarBlue (R) and relative protection from 6-hydroxydopamine was normalized to 6-hydroxydopamine treated cells in the absence of compound. Was measured by calculating the proportion of.

Neuroprotection observed in PC12 cells treated with the dual-acting FKBP12 and FKBP52 inhibitory example compounds CAP01687 (FIG. 1A) and CAPO 1693 (FIG. 1B) measured using the WST-8 assay. See 1B.
Specifically, FIGS. 1A and 1B show the relative protection from 6-OHDA, and the vehicle control is set to 0% relative protection. Demonstration of neuroprotection of wild-type a-synuclein overexpressing BE (2) -M17 as a result of treating cells with the exemplary compound CAP01687, which inhibits dual-acting FKBP12 and FKBP52, as measured by the Aramar Blue assay. See FIG. 3A for more information. Neuroprotection was also observed with the A53T mutant α-synuclein overexpressing BE (2) -M17 cells (M3.2) treated with CAP01687 (FIG. 3B). The bars in FIGS. 3A and 3B show relative percent fluorescence proportional to cell viability and the vehicle control is 100%.

Neurite Elongation PC12 rat chromaffin cell tumors or SH-SY5Y human neuroblastoma cells were grown on a cover glass of a 24-well cell culture dish in a humidified incubator at _{37 ° C. and 5% CO 2.} After 24 hours, the cells were washed with phosphate buffered saline to reduce the serum concentration in the growth medium to 0.2%. After 16 hours in reduced serum medium, 0.1% dimethyl sulfoxide (vehicle control) or a compound dissolved in dimethyl sulfoxide was added to growth medium. After 2 hours of exposure to the compound, the growth medium was prepared with 0.1% dimethyl sulfoxide (vehicle control) or a compound dissolved in dimethyl sulfoxide plus a neurogrowth factor (or phosphate buffered saline vehicle control). 6-Hydroxydopamine (or 0.1% ascorbic acid vehicle control) was supplemented. After 24 hours of incubation, medium was removed, replaced with ice-cold methanol and cells were incubated at −20 ° C. for 10 minutes. The cells were washed twice with phosphate buffered saline and placed on a slide for light microscopy. Phase-difference images were captured at 20x magnification and ImageJ software was used to record the proportion of cells with neurites longer than 20 μm for about 200 cells under each condition. See FIGS. 3A and 3B for the promotion of neurite outgrowth by the double-acting FKBP12 and FKBP52 inhibitory exemplary compounds CAP01687.

Preparation of 2- [2- (4-fluorophenyl) vinyl] -1- (4-methylbenzyl) -1H-benzimidazole (CAP01551) of 2- [2- (4-fluorophenyl) vinyl-1H-benzimidazole) Preparation (1) (Scheme 1)
4.32 g (40 mmol) of 1,2-phenylenediamine and concentrated HCl (30 mL) were added to a solution of 4.98 g (30 mmol) of 4-fluorocinnamic acid in ethylene glycol (40 mL). The mixture was heated to 125-135 ° C. for 4 hours. The reaction was cooled to room temperature, diluted with water and made basic with _{concentrated NH 4 OH.} The resulting precipitate was collected by filtration and recrystallized from ethanol / water. Yield: 6.22 g (87%).

Preparation of 2- [2- (4-fluorophenyl) vinyl] -1- (4-methylbenzyl) -1H-benzimidazole (CAP01551) 2- [2- (4-fluorophenyl) vinyl-1H-benzimidazole ( 4.77 g, and 20 mmol), was treated with DMF (in the presence of anhydrous of _K 2 CO ₃ 100ml) in 3.45 g (25 mmol) 4-methyl-benzyl chloride (3.10g, 22mmol). The mixture was heated to 110 ° C. and stirred for 6 hours. The solvent was removed by evaporation and the crude product was washed with water and recrystallized from hexane. (Yield 4.65 g (68%) as white crystals).
¹ HNMR (500 MHz, DMSO-de) δ 2.25 (s, 3 H), 5.21 (s, 2 H), 7.02-7.38 (m, 8 H), 7.50-7.64 (m, 3 H), 7.81 -7.89 (m, 3 H); ESI-MS: m / z 343 (M + H) +.

Preparation of 1-[(4-Methylphenyl) Methyl] -2- (2-Phenylethynyl) -1H-L3-benzodiazole (3, SKD-II-35) 2- (2-Phenylethynyl) -1H- Synthesis of 1,2-benzodiazole (2)
This compound was synthesized using Scheme 3.
The mixture 1,2-phenylenediamine (1.15 g, 10.06 mmol), phenylpropiolic acid (1.10 g, 7.56 mmol), concentrated HCl (8 ml) in ethylene glycol (10 mL) was stirred at 130 ° C. for 6 hours. .. The reaction mixture was cooled to room temperature, diluted with water and basified with concentrated NH 4 _0H. The reaction mixture was extracted with ethyl acetate, dried over sulfonyl ₄ and concentrated in vacuo. The residue was purified on a silica gel column using a hexane-ethyl acetate system to give compound 2 (60%).
^{1 1} HNMR (500 MHz, DMSO-de) δ 7.23-7.25 (m, 2 H), 7.48-7.54 (m, 3 H), 7.62-7.64 (m, 2 H), 7.84-7.86 (m, 2 H) , 12.43 (br s, 1 H, NH).

Synthesis of 1-[(4-methylphenyl) methyl] -2- (2-phenylethynyl) -1H-1,3-benzodiazole (3, SKD-11-35) 2 (64 mg, 0.29 mmol), A mixture of 4-methylbenzyl chloride (45 mg, 0.31 mmol) and K ₂ CO ₃ (52 mg, 0.37 mmol) in DMF (2 mL) was stirred at 110 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, the mixture was extracted with ethyl acetate, washed with brine (6x50 ml) and dried (0054 ₄ ). The residue was recrystallized from hexane. Yield: 75%.
^{1 1} HNMR (500 MHz, DMSO-de) δ 2.23 (s, 3 H, CH3), 5.62 (s, 2 H), 7.14 (d, J = 8.2 Hz, 2 H), 7.22 (d, J = 8.2 Hz) , 2 H), 7.27-7.32 (m, 2 H), 7.50-7.53 (m, 3 H), 7.62-7.70 (m, 4 H), ESI-MS: m / z 345 (M + Na) +, 323 (M + H) +.

Ki putative ligand binding was measured in combination with the recombinant full length FKBP12 and FKBP52 by fluorescent polarization of a fluorescein isothiocyanate (FITC) labeled probe (described in Bollini et al 2002). A binding saturation experiment was performed to determine the probe Kd of FKBP12 or FKBP52 using GraphPad software. Ligand substitution of FKBP12 or FKBP52 is measured by fluorescence polarization in the presence of varying concentration of compound, _{IC 50} of each compound using GraphPad software has been determined. IC ₅₀ values for each compound was used to estimate the Kj using the equations given by Nikolovska-Coleska, et al. 2004 . Nikolovska-Coleska, using the formulas described et al. 2004, were estimated Kj using IC ₅₀ values for each compound.

See Tables 2 and 3 below.

BE (2) -M17 human nerve designed to stably express either neuroprotective wild-type or A53T mutant α-synuclein, PC12 rat chromaffin cell tumor, or SH-SY5Y human neuroblastoma cells Neuroblastoma cells were cultured in 96-well cell culture dishes at 37 ° C. and in a humidified incubator with _{5% CO 2.} Growth medium was supplemented with 0.1% dimethyl sulfoxide (medium control) or a compound dissolved in dimethyl sulfoxide. After 2 hours of exposure to the compound, the growth medium was further supplemented with 6-hydroxydopamine (OHDA) or 0.1% ascorbic acid (medium control) and incubated for an additional 24-48 hours. Cell viability was measured by reduction of WST-8 or alamarBlue (R) and relative protection from 6-hydroxydopamine was normalized to 6-hydroxydopamine treated cells in the absence of compound. Was measured by calculating the proportion of. Neuroprotection obtained by treating wild-type α-synuclein overexpressing cells (WT21) cells with the dual-acting FKBP12 and FKBP52 inhibitory example compounds CAP01551 (FIG. 4A) and CAP01559 (FIG. 4B) is shown in FIGS. 4A and 4B. Please refer to. Neuroprotection can also be seen in Figure 5, which shows the results of treating A53T mutant α-synuclein overexpressing cells (M3.2) with CAP01559.

Neurite-extended PC12 rat chromaffin cell tumors or SH-SY5Y human neuroblastoma cells were grown on a cover glass of a 24-well cell culture dish in a humidified incubator at _{37 ° C. and 5% CO 2.} After 24 hours, the cells were washed with phosphate buffered saline to reduce the serum concentration in the growth medium to 0.2%. After 16 hours in reduced serum medium, 0.1% dimethyl sulfoxide (medium control), or a compound dissolved in dimethyl sulfoxide, was added to the growth medium. After 2 hours of exposure to the compound, in addition to 0.1% dimethyl sulfoxide (medium control) or the compound dissolved in dimethyl sulfoxide, the growth medium was 6-hydroxydopamine (OHDA) or 0.1% of neurogrowth factor. Supplemented with ascorbic acid vehicle control (or phosphate buffered physiological saline control). After 24 hours of incubation, medium was removed, replaced with ice-cold methanol and cells were incubated at −20 ° C. for 10 minutes. The cells were washed twice with phosphate buffered saline and placed on a slide for light microscopy. Phase-difference images were captured at 20x magnification and ImageJ software was used to record the proportion of cells with neurites longer than 20 μm for about 200 cells under each condition. See FIGS. 6C and 6D for the promotion of neurite outgrowth by the exemplary compound CAP01510, which inhibits dual-acting FKBP12 and FKBP52.

抗凝固剤としてＫ２−ＥＤＴＡの存在下で遠心分離することにより、血漿サンプルを分離した。脳組織をリン酸塩緩衝生理食塩水で均質化し、標準的な慣行に従って生物分析のために処理した。サンプルは、ＬＣ−ＭＳ／ＭＳ法を使用した発見グレードのバイオ分析法によって分析された。得られた結果を以下に示す。

注：結果は平均±ＳＤで表され、ｎ＝５匹の動物／時間／ポイント。離散法サンプリング１時間後の血液サンプリング後、動物の首を切り、ＬＣ−ＭＳ分析のために脳サンプルを回収した。

Distribution of inhibitors in plasma and brain After intravenous administration of inhibitors to mice, the distribution of inhibitors in plasma and brain tissue was examined. The experimental conditions were as follows. Mouse: Male CD1 about 8 weeks old. Weight: about 25 grams. Number of groups: 1. Number of animals per group: 5. Medium for intravenous administration:
DMSO; Dosage: 1 mg / kg. Samples were collected at the time shown in Table 4 below.

Plasma samples were separated by centrifugation in the presence of K2-EDTA as an anticoagulant. Brain tissue was homogenized with phosphate buffered saline and treated for bioanalysis according to standard practices. Samples were analyzed by discovery-grade bioanalysis using LC-MS / MS method. The results obtained are shown below.

Note: Results are expressed as mean ± SD, n = 5 animals / hour / point. After blood sampling 1 hour after discrete sampling, animals were decapitated and brain samples were collected for LC-MS analysis.

Microsome Stability Analysis Microsome stability measurements were performed by the Clint assay. The test compound was incubated with liver microsomes and metabolic stability was measured over 45 minutes. The experimental conditions were as follows. Compound concentration: 1 μM; Assay conditions: 100 mM potassium phosphate buffer pH 7.4 with 1 mM NADPH; Incubation time: 0, 5, 10, 15, 30, and 45 minutes at 37 ° C. Species: rat (male SD) and human (pooled mixed gender); protein concentration in assay: 0.5 mg / mL; analysis: LC-MS / MS; QC compound: verapamil (high clearance), atenolol (low clearance) ); And results: Clint (μL / min / mg protein), half-life (minutes). The measurement results are shown in Table 7 below.

reference:
Bollini S, Herbst JJ, Gaughan GT, Verdoorn TA, Ditta J, Dubowchik GM, Vinitsky A. (2002) J Biomol Screen. Dec; 7 (6): 526-30.
Deleersnijder A, Van Rompuy AS, Desender L, Pottel H, Buee L, Debyser Z, Baekelandt V, Gerard M. (2011). J Biol Chem. 286 (30): 26688-26701.
Gerard M, Debyser Z, Desender L, Kahle PJ, Baert J, Baekelandt V, Engelborghs Y (2006) α-synuclein aggregation is stimulated by the FK506 binding protein shown by fluorescence correlation spectroscopy.
Gerard M, Debyser Z, Desender L, Baert J, Brandt I, Baekelandt V, Engelborghs Y (2008) FK506 binding protein 12 specifically accelerates fibril formation of wild-type α-synuclein and its clinical mutations A30P or A53T. .. J Neurochem 106: 121-133.
Gerard M, Deleersnijder A, Daniels V, Schreurs S, Munck S, Reumers V, Pottel H, Engelborghs Y, Van den Haute C, Taymans JM, Debyser Z, Baekelandt V. (2010). J Neurosci., 30 (7) : 2454-2463.
Gerard M, Deleersnijder A, Demeulemeester J, Debyser Z, Baekelandt V. (2011).
Mol Neurobiol. 44 (1): 13-27.
Gothel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerase, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55: 423-436
Galat A (2003) Peptidyl prolylsis / transisomerase (immunophilin): biodiversity-target-function.
Curr Top Med Chem 3: 1315-1347
Nikolovska-Coleska Z, Wang R, Fang X, Pan H, Tomita Y, Li P, Roller PP, Krajewski K, Saito NG, Stuckey JA, Wang S. (2004) Anal Biochem. Sep 15; 332 (2): 261 -73.
Rulten SL, Kinloch RA, Tateossian H, Robinson C, Gettins L, Kay JE (2006) Human FK506 binding protein: characterization of human FKBP19. Mamm Genome 17: 322-331.
Souvik Chattopadhaya, Amaravadhi Harikishore, Ho Sup Yoon (2012). Role of FKBP in Parkinson's Disease, Mechanism of Parkinson's Disease-Models and Treatment, Dr. Juliana Dushanova (eds.), ISBN: 978-953-307-876-2, InTech, DOI: 10.5772 / 22419. Available from http://www.intechopen.com/books/mechanisms-in-parkinson-s-disease-models-and-treatments/role-of-fkbps-in-parkinson-s-disease.
Charters AR, Kobayashi M, Butcher SP (1994a) Immunochemical analysis of FK506 binding proteins in neuronal cell lines and rat brain. Biochem Soc Trans 22:41 IS
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Other Embodiments All features disclosed herein can be combined in any combination. Each property disclosed herein can be replaced with an alternative property that serves the same, equivalent, or similar purpose. Therefore, unless otherwise stated, each disclosed property is merely an example of a general series of equivalent or similar properties.
From the above description, one of ordinary skill in the art can easily confirm the essential features of the present invention, make various modifications and modifications of the present invention without departing from the spirit and scope thereof, and various uses and conditions. Can be adapted to. Therefore, other embodiments are also within the scope of the appended claims.

Claims (76)

Compound represented by formula (I)

Or its pharmaceutically acceptable salt,
In the formula, ^{R 1} is one or more optionally substituted cycloalkyl in groups, aryl or heteroaryl group, independently selected from ^{R 4, R 4} _{is, (C} 1- _C 6) Alkoxy; Halo (C _1- C ₆ ) Alkoxy; (C _2- C ₆ ) Alkoxy; Halo (C _2- C ₆ ) Alkoxy; (C _2- C ₆ ) Alkoxyl; Halo (C _2- C ₆ ) Alkoxyl; _(C 1 -C ₆₎ alkoxy; halo _(C 1 -C _{6) alkoxy; (C} 1 -C ₆₎ alkylthio; halo _(C 1 -C _{6) alkylthio; (C} 1 -C ₆₎ alkylsulfinyl; halo ( C _1- C ₆ ) Alkoxy Sulfinyl; (C _3- C ₆ ) Cycloalkyl Sulfinyl; Halo (C _3- C ₆ ) Cycloalkyl Sulfinyl; (C _1- C ₆ ) Alkoxy sulfonyl; Halo (C _1- C ₆ ) Alkoxysulfonyl; (C _3- C ₆ ) cycloalkylsulfonyl; halo (C _3- C ₆ ) cycloalkylsulfonyl; (C _1- C ₆ ) alkyl amino; di (C _1- C ₆ ) alkyl amino; (C ₁₎ -C ₆ ) Alkoxy (C _1- C ₆ ) Alkoxy; Halo (C _1- C ₆ ) Alkoxy (C _1- C ₆ ) Alkoxy; (C _1- C ₆ ) Alkoxy carbonyl; Amino carbonyl; H ₂ NSO ₂ ; _(C 1 -C ₆₎ alkylaminocarbonyl; di _(C 1 -C _{6) alkylaminocarbonyl; (C} 1 -C ₃₎ alkoxy _(C 1 -C ₃₎ alkyl aminocarbonyl; _{heterocyclylcarbonyl; (C} 1 -C ₆₎ alkylaminosulfonyl, di _(C 1 -C ₆₎ alkyl aminosulfonyl; _{heterocyclylsulfonyl; (C} 1 -C _{6) alkylcarbonylamino; (C} 1 -C ₆₎ alkylcarbonylamino _(C 1 -C ₆₎ alkyl ; _(C 1 -C _{6) alkylsulfonylamino; (C} 1 -C ₆₎ alkylsulfonylamino _(C 1 -C _{6) alkyl; (C} 1 -C ₆₎ alkoxycarbonyl _(C 1 -C ₆₎ alkoxy; ( C ₁ -C ₆₎ alkoxy _(C 1 -C ₆₎ alkyl, halo _(C 1 -C ₆₎ alkoxy _(C 1 -C ₆₎ alkyl; hydroxy _(C 1 -C ₆ ) Alkoxy; Amino (C _1- C ₆ ) Alkyl; (C _1- C ₆ ) Alkyl Amino (C _1- C ₆ ) Alkyl; Di (C _1- C ₆ ) Alkyl Amino (C _1- C ₆ ) Alkyl (C _1- C ₆ ) alkylamino (C _2- C ₆ ) alkoxy; di (C _1- C ₆ ) alkyl amino (C _2- C ₆ ) alkoxy; (C _1- C ₆ ) alkyl carbonyl; hydroxy ( C _1- C ₆ ) Alkyl carbonyl; (C _1- C ₆ ) Alkyl hydroxy carbonyl; (C _1- C ₆ ) Alkyl hydroxy (C _1- C ₆ ) Alkyl; (C _3- C ₆ ) Cycloalkyl carbonyl; (C 3-C 6) Cycloalkyl carbonyl; C _3- C ₆ ) cycloalkylaminocarbonyl; {(C _3- C ₆ ) cycloalkyl} {(C _1- C ₆ ) alkyl} aminocarbonyl; di (C _3- C ₆ ) cycloalkyl aminocarbonyl; (C _3- C ₆ ) Cycloalkylaminosulfonyl; {(C _3- C ₆ ) cycloalkyl} {(C _1- C ₆ ) alkyl} aminosulfonyl; di (C _3- C ₆ ) cycloalkyl aminosulfonyl; cyano (C) _1- C ₆ ) Alkyl; Aminocarbonyl (C _1- C ₆ ) Alkyl; (C _1- C ₆ ) Alkyl Aminocarbonyl (C _1- C ₆ ) Alkyl; Di (C _1- C ₆ ) Alkyl Aminocarbonyl (C _1- C ₆ ) Alkyl; (C _3- C ₆ ) Cycloalkyl Aminocarbonyl (C _1- C ₆ ) Alkyl; {(C _3- C ₆ ) Cycloalkyl} {(C _1- C ₆ ) Alkyl} Aminocarbonyl (C _1- C ₆ ) Alkyl; [C _1- C ₆ ) Alkyl (C _4- C ₆ ) Heterocyclyl] (C _1- C ₆ ) Alkyl; and Di (C _3- C ₆ ) Cycloalkyl Aminocarbonyl (C 3-C 6) _1- C ₆ ) Consists of alkyl;
R ² is a cycloalkyl or aromatic ring optionally substituted with one or more groups independently selected from ^{R 5;}
R ³ , R ⁴ , and R ⁵ are halo; cyano; nitro; amino; hydroxy; carboxy; (C _1- C ₆ ) alkyl; halo (C _1- C ₆ ) alkyl; (C _1- C ₆ ) hydroxyalkyl _{; (CH 2) 1-3 COOH;} (C 1 -C 6) alkoxy; halo _(C 1 -C _{6) alkoxy; (C} 1 -C ₆₎ alkylthio; halo _(C 1 -C ₆₎ alkylthio; (C _1- C ₆ ) Alkoxy sulfinyl; Halo (C _1- C ₆ ) Alkoxy sulfinyl; (C _1- C ₆ ) Alkoxy sulfonyl; Halo (C _1- C ₆ ) Alkoxy sulfonyl; (C _1- C ₆ ) Alkoxy amino; Di (C _1- C ₆ ) alkylamino; (C _2- C ₄ ) alkoxycarbonyl; (C _2- C ₄ ) alkyl aminocarbonyl; di (C _2- C ₄ ) alkyl aminocarbonyl; (C _3- C ₆₎ ) Cycloalkyl; halo (C _3- C ₆ ) cycloalkyl; (C _3- C ₆ ) cycloalkoxy; halo (C _3- C ₆ ) cycloalkoxy; aryl optionally substituted with halogen, OH, NH _2. Aryloxy; (C _1- C ₆ ) alkylthio; halo (C _1- C ₆ ) alkyl thio; (C _3- C ₆ ) cycloalkyl thio; halo (C _3- C ₆ ) cycloalkyl thio; (C _1- C ₆₎ ) alkylamino; and di _(C 1 -C ₆₎ is independently selected from alkyl group,
R ⁶ is hydrogen, (C _1- C ₆ ) alkyl, or halo (C _1- C ₆ ) alkyl.
X is O or H,
Z is CH ₂ or C = 0,
n is a number from 0 to 4
p is a number from 1 to 5
B and Y are independently CH or N. The compound according to claim 1, wherein n is 0, 1, or 2. The compound according to claim 1, wherein n is 0, 1 or 2, and p is 2 or 3. The compound according to claim 3, wherein B and Y are CH. R ² is a cycloalkyl group, A compound according to claim 4. The compound according to claim 5, wherein the cycloalkyl group has 5 or 6 ring carbon atoms. The compound according to claim 4, wherein R ^{2 is an aryl group.} The compound according to claim 7, wherein the aryl group is a phenyl group. The compound according to claim 8, wherein n is 1 or 2. The compound according to any one of claims 1 to 9, wherein R ^{5 is a halogen.} The compound according to any one of claims 1 to 9, wherein R ^{1 is a cycloalkyl group.} The compound according to claim 11, wherein the cycloalkyl group is adamantane. The compound according to any one of claims 1 to 9, wherein R ^{1 is an aryl group.} The compound according to claim 13, wherein the aryl group is a naphthyl group. The compound according to claim 13, wherein R ^{4 is a halogen.} The compound according to claim 13, wherein R ¹ is naphthyl and R ^{4 is halogen.} The compound according to claim 13, wherein R ⁴ is a C _1- C _{6 alkoxy group.} R ⁴ is a methoxy group, A compound according to claim 17. The compound according to any one of claims 1 to 9, wherein R ^{1 is an indazole group.} R ⁴ is an aryl group, The compound of claim 19. The compound according to any one of claims 1 to 9, wherein R ^{1 is an indole group.} The compound according to any one of claims 1 to 9, wherein R ^{1 is a phenyl-substituted aryl group.} The compound according to any one of claims 1 to 9, wherein R ^{1 is a phenoxy-substituted aryl group.} The compound according to any one of claims 1 to 9, wherein R ^{1 is a benzimidazole group.} The compound according to any one of claims 1 to 9, wherein R ³ is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to claim 19, wherein R ³ is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to claim 21, wherein R ³ is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to claim 22, wherein R ³ is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to claim 23, wherein R ³ is H, R ⁴ is a halogen or C 1 to C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to claim 24, wherein R ³ is H, R ⁴ is a halogen or C _{1 to} C ₆ alkoxy, and R ^{5 is a halogen.} The compound according to any one of claims 1 to 3, wherein B is CH and Y is N. The compound according to claim 31, wherein R ^{1 is an aryl group.} The compound according to claim 32, wherein the aryl group is naphthyl. R ² is an aryl group, The compound of claim 33. The compound according to claim 34, wherein R ^{4 is a halogen.} R ⁵ is halogen, 34. A compound according. The compound according to claim 36, wherein each of R ⁴ and R ^{5 is a halogen.} R ² is a cycloalkyl group, A compound according to claim 31. The compound according to claim 38, wherein the cycloalkyl group has 5 or 6 ring carbon atoms. The compound according to claim 31, wherein X is O and R ¹ is a branched five carbon alkyl groups. A compound having a formula selected from the following

Or its pharmaceutically acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of treating Parkinson's disease in a subject, therapeutic of the compound according to any one of claims 1-41 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 42. The method comprising administering to a subject an effective amount. 10. One of claims 1-41, wherein the lipid and nonionic surfactant, and an effective amount of an absorption enhancer that allows nasal absorption of the pharmacologically effective amount of the compound, are combined. A pharmaceutical composition for nasal administration containing a compound or a pharmaceutically acceptable salt thereof. The composition according to claim 44, wherein the absorption enhancer is a cationic polymer. The composition according to claim 45, wherein the cationic polymer is chitosan. A therapeutically effective amount of a pharmaceutical composition for nasal administration comprising the compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, which is a method for treating Parkinson's disease of interest. The method comprising administering to a subject in combination with a lipid and a nonionic surfactant, and an effective amount of an absorption enhancer that allows nasal absorption of a pharmacologically effective amount of the compound. 47. The method of claim 47, wherein the absorption enhancer is a cationic polymer. 48. The method of claim 48, wherein the cationic polymer is chitosan. Compound represented by formula II):

Or a pharmaceutically acceptable salt thereof _{, wherein each of R 1} and R _{3 in} the formula is hydrogen; halogen; nitro; cyano; amino; hydroxy; carboxy; (C _1- C ₆ ) alkyl; halo ( C _1- C ₆ ) alkyl; (C _1- C ₆ ) alkoxy; halo (C _1- C ₆ ) alkoxy; (C _3- C ₁₀ ) cycloalkyl; halo (C _3- C ₁₀ ) cycloalkyl; (C 3-C 10) cycloalkyl; _3- C ₁₀ ) Cycloalkylthio; Halo (C _3- C ₁₀ ) Cycloalkylthio; (C _3- C ₁₀ ) Heterocycloalkyl; Halo (C _3- C ₁₀ ) Heterocycloalkyl; (C _1- C ₆ ) Alkyl Amino; di (C _1- C ₆ ) alkyl amino; (C _1- C ₆ ) alkyl thio; halo (C _1- C ₆ ) alkyl thio; (C _1- C ₆ ) alkyl sulfinyl; halo (C _1- C ₆ ) Alkyl sulfinyl; (C _1- C ₆ ) alkylsulfonyl; halo (C _1- C ₆ ) alkylsulfonyl; (C _3- C ₁₀ ) cycloalkyl sulfinyl; halo (C _3- C ₁₀ ) cycloalkyl sulfinyl; (C ₃₎ -C ₁₀ ) cycloalkylsulfonyl; halo (C _3- C ₁₀ ) cycloalkylsulfonyl; halogen, nitro, cyano, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkyl , (C _1- C ₆ ) alkoxy, or _{aryl, heteroaryl, arylamine, or heterocyclyl optionally substituted with halo (C 1-} C ₆ ) alkoxy, and aryl rings fused to the associated phenyl ring. Rings are halogen, nitro, cyano, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C _1- C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, halo (C _1- C _6). ) Arbitrarily substituted with alkoxy or arylamines and selected independently from the group consisting of;
XY is C = C, C≡C, or N = N,
R ₂ is (C _1- C ₆ ) alkyl; halo (C _1- C ₆ ) alkyl; (C _2- C ₆ ) alkenyl; halo (C _2- C ₆ ) alkyne; (C _2- C ₆ ) alkynyl. Halo (C _2- C ₆ ) alkynyl; (C _3- C ₁₀ ) cycloalkyl;
Halo (C _3- C ₁₀ ) cycloalkyl; selected from the group consisting of heterocyclyl, aryl, or heteroaryl, halogen, nitro, cyano, amino, hydroxy, carboxy, (C _1- C ₆ ) alkyl, halo (C), respectively. _{It may be optionally substituted with 1-} C ₆ ) alkyl, (C _1- C ₆ ) alkoxy, and halo (C _1- C ₆ ) alkoxy; and m is 0-4. XY is C = C, m is 0 to 3, R ₂ is halogen, (C _1- C ₆ ) alkyl, halo (C _1- C ₃ ) alkyl, (C _1- C ₆ ) alkoxy. or halo is (C 1 _{-C 6)} aryl optionally substituted with alkoxy, a compound according to claim 50. The compound according to claim 51, wherein the aryl is a phenyl optionally substituted with a halogen, (C _1- C ₆ ) alkyl, or halo (C _1- C _{6) alkyl.} X-Y is C [identical to] C, m is 1, _{R 2} is _(C 2 -C ₆₎ alkenyl or _(C 2 -C ₆₎ alkynyl, A compound according to claim 50. R ₂ is _(C 2 -C ₆₎ alkenyl compound of claim 53. R ₂ is _(C 2 -C ₆₎ alkynyl, the compound of claim 53. The compound according to claim 50, wherein R ₃ is (C _1- C ₆ ) alkyl amino or di (C _1- C _{6) alkyl amino.} R ₃ is a di _(C 1 -C ₆₎ alkylamino, a compound according to claim 56. The compound according to claim 57, wherein R ₃ is N (CH ₃ ) _2. The compound according to claim 56, wherein R ₂ is (C _1- C _{6) alkyl.} The compound according to claim 51, wherein m is 0 to 2, R ₃ is a halogen, and R ₂ is a (C _1- C ₆ ) alkyl or a halo (C _1- C _{6) alkyl.} The compound according to claim 51, wherein R _{1 is hydrogen.} The compound according to claim 61, wherein R ₂ is a phenyl optionally substituted with a halogen. The compound according to claim 53, wherein R _{1 is hydrogen.} R ₂ is _(C 2 -C ₆₎ alkenyl compound of claim 63. The compound according to claim 56, wherein R _{1 is hydrogen.} R ₃ is a di _(C 1 -C ₆₎ alkylamino, a compound according to claim 65. The compound according to claim 60, wherein R _{1 is hydrogen.} The compound according to claim 50, which has a formula selected from the group consisting of:

Or its pharmaceutically acceptable salt. A pharmaceutical composition comprising the compound according to any one of claims 50 to 68 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a subject, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 50-68 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 69. How to treat Parkinson's disease. The compound according to any one of claims 50 to 68 or a pharmacy thereof in combination with an effective amount of a lipid and a nonionic surfactant and an absorption enhancer that enables a pharmacologically effective amount of nasal absorption. A pharmaceutical composition for nasal administration containing a nasally acceptable salt. The composition according to claim 71, wherein the absorption enhancer is a cationic polymer. The composition according to claim 72, wherein the cationic polymer is chitosan. The compound according to any one of claims 50 to 68, in combination with an effective amount of a lipid and a nonionic surfactant, and an absorption enhancer that allows nasal absorption of a pharmacologically effective amount of the compound. Alternatively, a method of treating Parkinson's disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutically acceptable salt thereof. The method of claim 74, wherein the absorption enhancer is a cationic polymer. The method of claim 75, wherein the cationic polymer is chitosan.

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